N4-acylcytosine nucleosides for treatment of viral infections

ABSTRACT

The present invention is directed to a method and composition of treating or preventing viral infections, in particular, human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections, in human patients or other animal hosts, comprising the administration of N.sup.4-acyl-2′,3′-dideoxy-5-fluorocytidine or N.sup.4-acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof.

The present application claims priority to U.S. patent application Ser.No. 10/318,511 filed on Dec. 13, 2002, which claimed priority to U.S.Patent Application Ser. No. 60/341,555 filed on Dec. 14, 2001.

FIELD OF THE INVENTION

The present invention is directed to compounds, methods and compositionsfor the treatment or prevention of viral infections using nucleosideanalogues. More specifically, the invention describesN.sup.4-acyl-substituted cytosine nucleoside analogues, pharmaceuticallyacceptable salts, prodrugs, or other derivatives thereof, and the usethereof in the treatment of a viral infection, and in particular a humanimmunodeficiency virus (HIV) or hepatitis B virus (HBV) infection.

BACKGROUND OF THE INVENTION

In 1981, acquired immune deficiency syndrome (AIDS) was identified as adisease that severely compromises the human immune system, and thatwithout exception leads to death. In 1983, the etiological cause of AIDSwas determined to be what is now known as human immunodeficiency virus(HIV).

Another virus that causes a serious human health problem is thehepatitis B virus (HBV). HBV is second only to tobacco as a cause ofhuman cancer. The mechanism by which HBV induces cancer is unknown. Itis postulated that it may directly trigger tumor development, orindirectly trigger tumor development through chronic inflammation,cirrhosis, and cell regeneration associated with the infection.

After a 2- to 6-month incubation period, during which the host istypically unaware of the infection, HBV infection can lead to acutehepatitis and liver damage, resulting in abdominal pain, jaundice andelevated blood levels of certain enzymes. HBV can cause fulminanthepatitis, a rapidly progressive, often fatal form of the disease inwhich large sections of the liver are destroyed.

Patients typically recover from the acute phase of HBV infection. Insome patients, however, high levels of viral antigen persist in theblood for an extended, or indefinite, period, causing a chronicinfection. Chronic infections can lead to chronic persistent hepatitis.Patients infected with chronic persistent HBV are most common indeveloping countries. By mid-1991, there were approximately 225 millionchronic carriers of HBV in Asia alone, and worldwide, almost 300 millioncarriers. Chronic persistent hepatitis can cause fatigue, cirrhosis ofthe liver, and hepatocellular carcinoma, a primary liver cancer.

In Western, industrialized countries, the high-risk group for HBVinfection includes those in contact with HBV carriers or their bloodsamples. The epidemiology of HBV is very similar to that of HIV/AIDS,which is a reason why HBV infection is common among patients infectedwith HIV or suffering from AIDS. However, HBV is more contagious thanHIV.

In 1985, it was reported that the synthetic nucleoside3′-azido-3′-deoxythymidine (AZT) inhibited the replication of HIV. Sincethen, several other synthetic nucleosides, including but not limited to2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxycytidine (ddC),2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T),(−)-2′,3′-dideoxy-3′-thiacytidine (3TC), and (−)-carbocyclic2′,3′-didehydro-2′,3′-dideoxyguanosine (carbovir) and its prodrugabacavir, have proven effective against HIV. After phosphorylation tothe 5′-triphosphate by cellular kinases, these synthetic nucleosides areincorporated into a growing strand of viral DNA, causing chaintermination, because they lack a 3′-hydroxyl group. Some nucleosidesalso inhibit the viral enzyme reverse transcriptase.

3TC (lamivudine) and interferon are currently the only FDA-approveddrugs for the treatment of HBV infection. Viral resistance developswithin 6 months of 3TC treatment in about 14% of patients.

Cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC) iscurrently in clinical trials for the treatment of HIV and separately forHBV by Triangle Pharmaceuticals, Inc. See Schinazi et al. (1992)Selective inhibition of human immunodeficiency viruses by racemates andenantiomers ofcis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine.Antimicrob. Agents Chemother. 36, 2423-2431; U.S. Pat. Nos. 5,210,085;5,914,331; 5,814,639; WO 91/11186; and WO 92/14743.

The success of 2′,3′-dideoxy- and2′,3′-didehydro-2′,3′-dideoxy-nucleosides (referred to as a “ddN” or“d2N” nucleoside and a “d4N” nucleoside, respectively) in inhibiting thereplication of HIV in vivo or in vitro has led a number of researchersto design and test a variety of modified d2- and d4-nucleosides. Onemodification has been the replacement of the 5-hydrogen on cytosinenucleosides with fluorine, resulting in several 5-fluorocytosinenucleosides with antiviral activity, including but not limited to β-D-and β-L-2′,3′-dideoxy-5-fluorocytine (β-D-D2FC and β-L-D2FC) (U.S. Pat.Nos. 4,788,181 and 6,156,737).

β-D-2′,3′-Dideoxy-2′,3′-didehydro-5-fluorocytidine (d4FC) and its use totreat hepatitis B was first described in Example 2 of European Pat.Application No. 0 409 227 A2 (Ajinomoto Co., Inc.). Netherlands Pat. No.8901258 (Stichting Rega V.Z.W.) discloses generally5-halogeno-2′,3′-dideoxy-2′,3′-didehydrocytidine derivatives for use intreating HIV and HBV. β-D- andβ-L-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine were furtherdescribed in U.S. Pat. Nos. 5,703,058; 5,905,070; 6,232,300; and5,561,120. U.S. Pat. No. 5,703,058 claims a method for the treatment ofHIV and/or HBV infection that includes administering an effective amountof β-L-d4FC in combination or alternation withcis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane,cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane,9-[4-(hydroxymethyl)-2-cyclopenten-1-yl)-guanine (carbovir),9-[(2-hydroxyethoxy)methyl]-guanine (acyclovir), interferon,3′-deoxy-3′-azido-thymidine (AZT), 2′,3′-dideoxyinosine (ddI),2′,3′-dideoxycytidine (ddC), (−)-2′-fluoro-5-methyl-β-L-ara-uridine(L-FMAU) or 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). U.S. Pat. No.5,905,070 claims a method for the treatment of HIV and HBV infectionthat includes administering an effective amount of β-D-d4FC incombination or alternation withcis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane,cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane,9-[4-(hydroxy-methyl)-2-cyclopenten-1-yl)-guanine (carbovir),9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), interferon,3′-deoxy-3′-azido-thymidine (AZT), 2′,3′-dideoxyinosine (ddI),2′,3′-dideoxycytidine (ddC), (−)-2′-fluoro-5-methyl-β-L-ara-uridine(L-FMAU) or 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). U.S. Pat. No.6,232,300 claims a method to treat HIV with β-D-d4FC.

Modification of the amino group of antiviral cytosine nucleosides hasnot been fully explored. Only a few N⁴-substituted cytosine2′,3′-dideoxy nucleosides and N⁴-substituted cytosine2′,3′-didehydro-2′,3′-dideoxy nucleosides have been reported. Theseinclude N⁴-benzoyl-2′,3′-didehydro-2′,3-dideoxycytidine (Kawaguchi etal., Studies on 2′,3′-dideoxy-2′,3′-didehydropyrimidine nucleosides. II.N⁴-benzoyl-2′,3′-dideoxy-2′,3′-didehydrocytidine as a prodrug of2′,3′-dideoxy-2′,3′-didehydrocytidine (DDCN), Chem. Pharm. Bull. (1989),37(9), 2547-9), N⁴-benzoyl-2′,3′-dideoxycytidine (Gulbis et al. (1993)Structure of a dideoxynucleoside active against the HIV (AIDS) virus.Acta Cryst. C49, 1095-1097),N⁴-acetyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, andN⁴-isopropyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (Shi et al.(1999)) Synthesis and biological evaluation of2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (d4FC) analogues:discovery of carbocyclic nucleoside triphosphates with potent inhibitoryactivity against HIV-1 reverse transcriptase. J. Med. Chem. 42,859-867). Of the sugar-modified cytosine nucleosides, some N⁴-acyl andimine-substituted 2′,3′-dideoxy-3′-C-hydroxymethylcytidine analogueshave been synthesized (Mauldin et al. (1998) Synthesis and antiviralactivity of prodrugs of the nucleoside1-[2′,3′-dideoxy-3′-C-(hydroxymethyl)-β-D-erythropentofuranosyl]cytosine.Bioorg. Med. Chem. 6, 577-585), and some N⁴-acetyl- andphosphonoacetyl-2′,3′-dideoxy-3′-thiacytidine nucleosides have beenprepared (Charvet et al. (1993) Inhibition of human immunodeficiencyvirus type I replication by phosphonoformate- andphosphonoacetate-2′,3′-dideoxy-3′-thiacytidine conjugates. J. Med. Chem.37, 2216-2223).

Therefore, it is an object of the present invention to provide a methodand composition for the treatment or prevention of HIV infection inhuman patients.

It is another object of the present invention to provide a method andcomposition for the treatment or prevention of HBV infection in humanpatients or other host animals.

It is still another object of the present invention to provide a methodand composition for the treatment or prevention of HIV and HBV infectionin human patients or other host animals.

SUMMARY OF THE INVENTION

It has been found that certain N⁴-acyl-cytosine nucleosides, and inparticular, N⁴-acyl-2′,3′-dideoxy-5-fluorocytidine andN⁴-acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-cytidine, show improvedinhibitory activity against HIV and HBV. Therefore, a method for thetreatment or prevention of HIV and/or HBV infection in a host, and inparticular, a human, is provided that includes administering aneffective amount of a N⁴-acyl-cytosine nucleoside.

In one embodiment of the invention, the active compound is of formula(I) or (II):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

-   -   i) X is O, S, NR⁵, CH₂, CHF or CF₂;    -   ii) Y is CH₂, CHF or CF₂;    -   iii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), cycloalkyl (including but not limited to C₃, C₄,        C₅, C₆, C₇, and C₈), CN, CF₃, N₃, NO₂, aryl (including but not        limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including but        not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂) and        acyl (including but not limited to C₂, C₃, C₄, C₅, and C₆);    -   iv) R² is chosen from alkyl (including but not limited to C₁,        C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅,        C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and C₂₂), alkenyl (including but        not limited to C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,        C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and C₂₂), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉,        C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and        C₂₂), cycloalkyl (including but not limited to C₃, C₄, C₅, C₆,        C₇, and C₈), aminoalkyl (including but not limited to C₁, C₂,        C₃, C₄, C₅, and C₆), hydroxyalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), aryl (including but        not limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including        but not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂),        and C₆H₄R⁶ where R⁶ is chosen from halogen (F, Cl, Br, I), CN,        CF₃, N₃, NO₂, alkyl (including but not limited to C₁, C₂, C₃,        C₄, C₅, and C₆), haloalkyl (including but not limited to C₁, C₂,        C₃, C₄, C₅, and C₆), aminoalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), alkoxy (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆), and aryl (including but        not limited to C₆, C₇, C₈, C₉, and C₁₀);    -   v) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆);    -   vi) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol; and    -   vii) R⁵ is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.

In one embodiment of the present invention, if the active compound is offormula (II), and X is O, S, CH₂, CHF or CF₂, R¹ is F, and R³ and R^(3′)are H or F, then R² cannot be an alkyl, alkoxyalkyl (such asmethoxymethyl), aralkyl (such as benzyl or substituted benzyl),aryloxyalkyl (such as phenoxymethyl) or aryl (including but not limitedto a phenyl optionally substituted with halogen (F, Cl, Br, I), alkyl(including but not limited to C₁, C₂, C₃, and C₄) or alkoxy (includingbut not limited to C₁, C₂, C₃, and C₄)).

The compound of the present invention can be in the form of the isolatedβ-L- or β-D-configuration, or a mixture thereof, including but notlimited to a racemic mixture. In one embodiment, Y is CH₂ and both R³and R^(3′) groups are hydrogen, forming a d2 nucleoside (i.e., a2′,3′-dideoxy nucleoside).

In one embodiment, the active compound isβ-D-N⁴-p-iodobenzoyl-2′,3′-dideoxy-5-fluorocytidine. Other specificexamples of active compounds includeβ-D-N⁴-p-fluoro-benzoyl-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-chlorobenzoyl-2′,3′-dideoxy-5-fluoro-cytidine,β-D-N⁴-p-bromobenzoyl-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-ethyl-benzoyl-2′,3′-dideoxy-5-fluorocytidine, andβ-D-N⁴-p-t-butylbenzoyl-2′,3′-dideoxy-5-fluoro-cytidine.

In another embodiment, the active compound isβ-D-N⁴-p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.Other specific examples of active compounds includeβ-D-N⁴-p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-chlorobenzoyl-2′,3′-didehydro-2′3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,andβ-D-N⁴-p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.

In addition, the 2′,3′-dideoxy-N⁴-acyl-cytosinenucleosides and2′,3′-didehydro-2′,3′-dideoxy-N⁴-acyl-cytosinenucleosides are inhibitorsof HBV. Therefore, these compounds can also be used to treat patientsthat are co-infected with both HIV and HBV.

The present invention provides a compound, method and composition fortreating an HIV infection in a host comprising administering atherapeutically effective amount of at least one compound as describedin the present application.

The present invention provides a compound, method and composition forpreventing an HIV infection in a host comprising administering atherapeutically effective amount of at least one compound as describedin the present application.

The present invention provides a compound, method and composition fortreating an HBV infection in a host comprising administering atherapeutically effective amount of at least one compound as describedin the present application.

The present invention provides a compound, method and composition forpreventing an HBV infection in a host comprising administering atherapeutically effective amount of at least one compound as describedin the present application.

In another aspect, there is provided a pharmaceutical formulationcomprising a compound of the invention in combination with apharmaceutically acceptable carrier or excipient for the treatment of ahost infected with HIV or HBV.

In still another aspect, there is provided a compound, method andcomposition for treating or preventing an HIV infection in a hostcomprising administering to the subject a combination comprising atleast one compound of the invention and at least one further therapeuticagent.

In still another aspect, there is provided a method and composition fortreating or preventing an HBV infection in a host comprisingadministering to the subject a combination comprising at least onecompound of the invention and at least one further therapeutic agent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a non-limiting example of the synthesis of active compounds ofthe present invention, and in particular, the synthesis ofβ-D-N⁴-acyl-2′,3′-dideoxy-5-fluorocytidine andβ-D-N⁴-acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine nucleosides.

FIG. 2 is a graphic representation of the anti-HBV activity of selectedN⁴-acyl-substituted β-D-2′,3′-dideoxy- andβ-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine analogues.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that N⁴-acyl-cytosine nucleosides, and in particular,N⁴-acyl-2′,3′-dideoxy-5-fluorocytidine andN⁴-acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, show improvedinhibitory activity against HIV and HBV. Therefore, a method for thetreatment or prevention of a host, and in particular, a human, infectedwith HIV and/or HBV, is provided that includes administering aneffective amount of an N⁴-acyl-cytosine nucleosides.

The present invention also provides a method and composition fortreating an HIV infection in a host comprising administering atherapeutically effective amount of at least one compound as describedin the present application.

The present invention provides a method and composition for preventingan HIV infection in a host comprising administering a therapeuticallyeffective amount of at least one compound as described in the presentapplication.

The present invention provides a method and composition for treating anHBV infection in a host comprising administering a therapeuticallyeffective amount of at least one compound as described in the presentapplication.

The present invention provides a method and composition for preventingan HBV infection in a host comprising administering a therapeuticallyeffective amount of at least one compound as described in the presentapplication.

In another aspect, there is provided a pharmaceutical formulationcomprising a compound of the invention in combination with apharmaceutically acceptable carrier or excipient.

In still another aspect, there is provided a method and composition fortreating or preventing an HIV infection in a host comprisingadministering to the subject a combination comprising at least onecompound of the invention and at least one further therapeutic agent.

In still another aspect, there is provided a method and composition fortreating or preventing an HBV infection in a host comprisingadministering to the subject a combination comprising at least onecompound of the invention and at least one further therapeutic agent.

I. ACTIVE COMPOUND

In one embodiment of the invention, the active compound is of formula(I) or (II):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

-   -   i) X is O, S, NR⁵, CH₂, CHF or CF₂;    -   ii) Y is CH₂, CHF or CF₂;    -   iii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), cycloalkyl (including but not limited to C₃, C₄,        C₅, C₆, C₇, and C₈), CN, CF₃, N₃, NO₂, aryl (including but not        limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including but        not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂) and        acyl (including but not limited to C₂, C₃, C₄, C₅, and C₆);    -   iv) R² is chosen from alkyl (including but not limited to C₁,        C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅,        C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and C₂₂), alkenyl (including but        not limited to C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,        C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and C₂₂), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉,        C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and        C₂₂), cycloalkyl (including but not limited to C₃, C₄, C₅, C₆,        C₇, and C₈), aminoalkyl (including but not limited to C₁, C₂,        C₃, C₄, C₅, and C₆), hydroxyalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), aryl (including but        not limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including        but not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂),        and C₆H₄R⁶ where R⁶ is chosen from halogen (F, Cl, Br, I), CN,        CF₃, N₃, NO₂, alkyl (including but not limited to C₁, C₂, C₃,        C₄, C₅, and C₆), haloalkyl (including but not limited to C₁, C₂,        C₃, C₄, C₅, and C₆), aminoalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), alkoxy (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆), and aryl (including but        not limited to C₆, C₇, C₈, C₉, and C₁₀);    -   v) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆);    -   vi) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol; and    -   vii) R⁵ is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.

The compound of the present invention can be in the form of the β-L- orβ-D-configuration, or a racemic mixture.

In one embodiment of the present invention, if the active compound is offormula (II), and X is O, S, CH₂, CHF or CF₂, R¹ is F, and R³ and R^(3′)are H or F, then R² cannot be an alkyl, alkoxyalkyl (such asmethoxymethyl), aralkyl (such as benzyl or substituted benzyl),aryloxyalkyl (such as phenoxymethyl) or aryl (including but not limitedto a phenyl optionally substituted with halogen (F, Cl, Br, I), alkyl(including but not limited to C₁, C₂, C₃, and C₄) or alkoxy (includingbut not limited to C₁, C₂, C₃, and C₄)).

In another particular sub-embodiment of the present invention, theactive compound is of formula (I), or a pharmaceutically acceptable saltor prodrug thereof, wherein

-   -   i) X is O;    -   ii) Y is CH₂, CHF or CF₂;    -   iii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), cycloalkyl (including but not limited to C₃, C₄,        C₅, C₆, C₇, and C₉), CN, CF₃, N₃, NO₂, aryl (including but not        limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including but        not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂) and        acyl (including but not limited to C₂, C₃, C₄, C₅, and C₆);    -   iv) R² is chosen from alkyl (including but not limited to C₁,        C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅,        C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and C₂₂), alkenyl (including but        not limited to C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,        C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and C₂₂), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉,        C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, and        C₂₂), cycloalkyl (including but not limited to C₃, C₄, C₅, C₆,        C₇, and C₈), aminoalkyl (including but not limited to C₁, C₂,        C₃, C₄, C₅, and C₆), hydroxyalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), aryl (including but        not limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including        but not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂),        and C₆H₄R⁶ where R⁶ is chosen from halogen (F, Cl, Br, I), CN,        CF₃, N₃, NO₂, alkyl (including but not limited to C₁, C₂, C₃,        C₄, C₅, and C₆), haloalkyl (including but not limited to C₁, C₂,        C₃, C₄, C₅, and C₆), aminoalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), alkoxy (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆), and aryl (including but        not limited to C₆, C₇, C₈, C₉, and C₁₀);    -   v) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   vi) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl, sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol.

In another particular sub-embodiment of the present invention, theactive compound is of formula (I), or a pharmaceutically acceptable saltor prodrug thereof, wherein

-   -   i) X is O;    -   ii) Y is CH₂, CHF or CF₂;    -   iii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), CN, CF₃, N₃, or NO₂;    -   iv) R² is chosen from cycloalkyl (including but not limited to        C₃, C₄, C₅, C₆, C₇, and C₈), aminoalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), heteroaryl        (including but not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,        and C₁₂), and C₆H₄R⁶ where R⁶ is chosen from halogen (F, Cl, Br,        I), CN, CF₃, N₃, NO₂, alkyl (including but not limited to C₁,        C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), aminoalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkoxy (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), and aryl        (including but not limited to C₆, C₇, C₈, C_(g), and C₁₀);    -   v) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   vi) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol.

In another particular sub-embodiment of the present invention, theactive compound is of formula (I), or a pharmaceutically acceptable saltor prodrug thereof, wherein

-   -   i) X is O;    -   ii) Y is CH₂, CHF or CF₂;    -   iii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), CN, CF₃, N₃, or NO₂;    -   iv) R² is chosen from cycloalkyl (including but not limited to        C₃, C₄, C₅, C₆, C₇, and C₈), aminoalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), heteroaryl        (including but not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,        and C₁₂);    -   v) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   vi) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol.

In another particular sub-embodiment of the present invention, theactive compound is of formula (I), or a pharmaceutically acceptable saltor prodrug thereof, wherein

-   -   i) X is O;    -   ii) Y is CH₂, CHF or CF₂;    -   iii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), CN, CF₃, N₃, or NO₂;    -   iv) R² is C₆H₄R⁶ where R⁶ is chosen from CN, CF₃, N₃, NO₂,        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), aminoalkyl (including but not limited to C₁, C₂, C₃, C₄,        C₅, and C₆), thioalkyl (including but not limited to C₁, C₂, C₃,        C₄, C₅, and C₆), alkenyl (including but not limited to C₂, C₃,        C₄, C₅, and C₆), alkynyl (including but not limited to C₂, C₃,        C₄, C₅, and C₆), and aryl (including but not limited to C₆, C₇,        C₈, C₉, and C₁₀);    -   v) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   vi) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol.

In another particular sub-embodiment of the present invention, theactive compound is of formula (I), or a pharmaceutically acceptable saltor prodrug thereof, wherein

-   -   i) X is O;    -   ii) Y is CH₂, CHF or CF₂;    -   iii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), CN, CF₃, N₃, or NO₂;    -   iv) R² is C₆H₄R⁶ where R⁶ is chosen from halogen (F, Cl, Br, I),        CN, CF₃, N₃, NO₂, alkyl (including but not limited to C₁, C₂,        C₃, C₄, C₅, and C₆), haloalkyl (including but not limited to C₁,        C₂, C₃, C₄, C₅, and C₆), aminoalkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkoxy (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including        but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl (including        but not limited to C₂, C₃, C₄, C₅, and C₆), and aryl (including        but not limited to C₆, C₇, C₈, C₉, and C₁₀);    -   v) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   vi) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol; and.

In a particular sub-embodiment of the present invention, the activecompound is of formula (II) or a pharmaceutically acceptable salt orprodrug thereof, wherein

-   -   i) X is O;    -   ii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), cycloalkyl (including but not limited to C₃, C₄,        C₅, C₆, C₇, and C₈), CN, CF₃, N₃, NO₂, aryl (including but not        limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including but        not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂) and        acyl (including but not limited to C₂, C₃, C₄, C₅, and C₆);    -   iii) R¹ is chosen from cycloalkyl (including but not limited to        C₃, C₄, C₅, C₆, C₇, and C₈), aminoalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), heteroaryl        (including but not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,        and C₁₂), and C₆H₄R⁶ where R⁶ is chosen from halogen (F, Cl, Br,        I), CN, CF₃, N₃, NO₂, alkyl (including but not limited to C₁,        C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), aminoalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkoxy (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), and aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀);    -   iv) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   v) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol.

In a particular sub-embodiment of the present invention, the activecompound is of formula (II) or a pharmaceutically acceptable salt orprodrug thereof, wherein

-   -   i) X is O;    -   ii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), CN, CF₃, N₃, and NO₂;    -   iii) R² is chosen from cycloalkyl (including but not limited to        C₃, C₄, C₅, C₆, C₇, and C₈), aminoalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), heteroaryl        (including but not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,        and C₁₂);    -   iv) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   v) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol.

In a particular sub-embodiment of the present invention, the activecompound is of formula (II) or a pharmaceutically acceptable salt orprodrug thereof, wherein

-   -   i) X is O;    -   ii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), cycloalkyl (including but not limited to C₃, C₄,        C₅, C₆, C₇, and C₈), CN, CF₃, N₃, NO₂, aryl (including but not        limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including but        not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂) and        acyl (including but not limited to C₂, C₃, C₄, C₅, and C₆);    -   iii) R² is C₆H₄R⁶ where R⁶ is chosen from halogen ((F, Cl, Br,        I), CN, CF₃, N₃, NO₂, alkyl (including but not limited to C₁,        C₂, C₃, C₄, C₅, and C₆), haloalkyl (including but not limited to        C₁, C₂, C₃, C₄, C₅, and C₆), aminoalkyl (including but not        limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkoxy (including but        not limited to C₁, C₂, C₃, C₄, C₅, and C₆), thioalkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), and aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀);    -   iv) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   v) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol.

In a particular sub-embodiment of the present invention, the activecompound is of formula (II) or a pharmaceutically acceptable salt orprodrug thereof, wherein

-   -   i) X is O;    -   ii) R¹ is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl        (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),        haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and        C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and        C₆), haloalkenyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), alkynyl (including but not limited to C₂, C₃, C₄, C₅,        and C₆), haloalkynyl (including but not limited to C₂, C₃, C₄,        C₅, and C₆), cycloalkyl (including but not limited to C₃, C₄,        C₅, C₆, C₇, and C₈), CN, CF₃, N₃, NO₂, aryl (including but not        limited to C₆, C₇, C₈, C₉, and C₁₀), heteroaryl (including but        not limited to C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, and C₁₂) and        acyl (including but not limited to C₂, C₃, C₄, C₅, and C₆);

-   iii) R² is C₆H₄R⁶ where R⁶ is chosen from CN, CF₃, N₃, NO₂,    haloalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and C₆),    aminoalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and    C₆), thioalkyl (including but not limited to C₁, C₂, C₃, C₄, C₅, and    C₆), alkenyl (including but not limited to C₂, C₃, C₄, C₅, and C₆),    alkynyl (including but not limited to C₂, C₃, C₄, C₅, and C₆), and    aryl (including but not limited to C₆, C₇, C₈, C₉, and C₁₀);    -   iv) R³ and R^(3′) are chosen independently from H, halogen (F,        Cl, Br, I), CN, CF₃, N₃, NO₂, alkyl (including but not limited        to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl (including but not        limited to C₂, C₃, C₄, C₅, and C₆), and alkynyl (including but        not limited to C₂, C₃, C₄, C₅, and C₆); and    -   v) R⁴ is H, phosphate (including but not limited to        monophosphate, diphosphate, triphosphate, or a stabilized        phosphate prodrug), carbonyl substituted with alkyl (including        but not limited to C₁, C₂, C₃, C₄, C₅, and C₆), alkenyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), alkynyl        (including but not limited to C₂, C₃, C₄, C₅, and C₆), aryl        (including but not limited to C₆, C₇, C₈, C₉, and C₁₀), or other        pharmaceutically acceptable leaving group, which, when        administered in vivo, is capable of providing a compound wherein        R³ and R^(3′) are H or phosphate, sulfonate ester (including but        not limited to alkyl or arylalkyl sulfonyl including but not        limited to methanesulfonyl), benzyl (wherein the phenyl group is        optionally substituted with one or more substituents as        described in the definition or aryl given above), a lipid        (including but not limited to a phospholipid), an amino acid, a        peptide, or cholesterol.

In one embodiment of the present invention, the active compound is offormula (I), its pharmaceutically acceptable salt or prodrugs thereof,wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I), CN, CF₃, N₃, NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy,thioalkyl, alkenyl, alkynyl, or aryl in the ortho position.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I) in the ortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Br in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with I in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with F in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Cl in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with NO₂ in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkyl in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with methyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with ethyl in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-propyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with iso-propyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-butyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with sec-butyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with tert-butyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-pentyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with isopentyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with neopentyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with cyclopentyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-hexyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with a cyclohexyl inthe ortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CN in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CF₃ in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with N₃ in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with haloalkyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aminoalkyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkoxy in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thioalkyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkenyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkynyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aryl in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thiophenyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with furanyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with naphthyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzoyl in theortho position.

In one embodiment of the present invention, the active compound is offormula (I), its pharmaceutically acceptable salt or prodrugs thereof,wherein:

i) X is O; Y is Cl₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I), CN, CF₃, N₃, NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy,thioalkyl, alkenyl, alkynyl, or aryl in the meta position.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I) in the meta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Br in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with I in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with F in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Cl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with NO₂ in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkyl in the meta,position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with methyl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with ethyl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-propyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula, its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with iso-propyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-butyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with sec-butyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with tert-butyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-pentyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with isopentyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with neopentyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with cyclopentyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-hexyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with a cyclohexyl inthe meta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CN in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CF₃ in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with N₃ in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with haloalkyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aminoalkyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkoxy in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thioalkyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkenyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkynyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aryl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzyl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thiophenyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with furanyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with naphthyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzoyl in themeta position.

In one embodiment of the present invention, the active compound is offormula (I), its pharmaceutically acceptable salt or prodrugs thereof,wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen,iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I), CN, CF₃, N₃, NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy,thioalkyl, alkenyl, alkynyl, or aryl in the para position.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I) in the para position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Br in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with I in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with F in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Cl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with NO₂ in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkyl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with methyl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with ethyl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-propyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with iso-propyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-butyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with sec-butyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with tert-butyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-pentyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with isopentyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with neopentyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with cyclopentyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-hexyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with a cyclohexyl inthe para position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CN in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CF₃ in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with N₃ in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with haloalkyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aminoalkyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkoxy in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thioalkyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkenyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkynyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aryl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzyl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R¹ and R³ are independently hydrogen or fluorine; R⁴ is hydrogen;andiv) R² is a phenyl moiety optionally substituted with thiophenyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with furanyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with naphthyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzoyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,6-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,5-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,4-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,5-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,5-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,6-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5,6-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4,5-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,4,5-tetrahalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with2,3,4,5,6-pentahalo.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,6-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,5-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,4-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,5-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,5-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,6-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5,6-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4,5-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with2,3,4,5-tetraalkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with2,3,4,5,6-pentaalkyl.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,6-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,5-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,4-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,5-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,5-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,6-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5,6-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (I), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4,5-tri-NO₂.

In one embodiment of the present invention, the active compound is offormula (II), its pharmaceutically acceptable salt or prodrugs thereof,wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I), CN, CF₃, N₃, NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy,thioalkyl, alkenyl, alkynyl, or aryl in the ortho position.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I) in the ortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Br in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with I in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with F in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Cl in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with NO₂ in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkyl in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with methyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with ethyl in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-propyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with iso-propyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-butyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with sec-butyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with tert-butyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-pentyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with isopentyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with neopentyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with cyclopentyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-hexyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with a cyclohexyl inthe ortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CN in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CF₃ in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with N₃ in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with haloalkyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aminoalkyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkoxy in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thioalkyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkenyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkynyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aryl in the orthoposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thiophenyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with furanyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with naphthyl in theortho position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzoyl in theortho position.

In one embodiment of the present invention, the active compound is offormula (II), its pharmaceutically acceptable salt or prodrugs thereof,wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I), CN, CF₃, N₃, NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy,thioalkyl, alkenyl, alkynyl, or aryl in the meta position.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I) in the meta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Br in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with I in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with F in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Cl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with NO₂ in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkyl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with methyl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with ethyl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-propyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with iso-propyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-butyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with sec-butyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with tert-butyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-pentyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with isopentyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with neopentyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with cyclopentyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-hexyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with a cyclohexyl inthe meta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CN in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CF₃ in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with N₃ in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with haloalkyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aminoalkyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkoxy in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thioalkyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkenyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkynyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aryl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzyl in the metaposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thiophenyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with furanyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with naphthyl in themeta position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzoyl in themeta position.

In one embodiment of the present invention, the active compound is offormula (II), its pharmaceutically acceptable salt or prodrugs thereof,wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I), CN, CF₃, N₃, NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy,thioalkyl, alkenyl, alkynyl, or aryl in the para position.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with halogen (F, Cl,Br, I) in the para position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Br in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with I in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with F in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with Cl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with NO₂ in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkyl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with methyl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with ethyl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-propyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with iso-propyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-butyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with sec-butyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with tert-butyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-pentyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with isopentyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with neopentyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with cyclopentyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with n-hexyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with a cyclohexyl inthe para position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CN in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with CF₃ in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with N₃ in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with haloalkyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aminoalkyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkoxy in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thioalkyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkenyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with alkynyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R¹ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with aryl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzyl in the paraposition.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with thiophenyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with furanyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with naphthyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with benzoyl in thepara position.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,6-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,5-dihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,4-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,5-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,5-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,6-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5,6-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4,5-trihalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,4,5-tetrahalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with2,3,4,5,6-pentahalo.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are, independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,6-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,5-dialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,4-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,5-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,5-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,6-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5,6-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4,5-trialkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with2,3,4,5-tetraalkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with2,3,4,5,6-pentaalkyl.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,6-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,5-di-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,4-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,3,5-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; and div) R² is a phenyl moiety optionally substituted with 2,4,5-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,4,6-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 2,5,6-tri-NO₂.

In yet another embodiment of the present invention, the active compoundis of formula (II), its pharmaceutically acceptable salts or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a phenyl moiety optionally substituted with 3,4,5-tri-NO₂.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a thienyl moiety optionally substituted with alkyl, halo,alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl in the 2-position.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a thienyl moiety optionally substituted with alkyl, halo,alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl in the 3-position or the 4-position.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a benzothiophenyl optionally substituted with alkyl, halo,alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl on the benzene ring.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a benzothiophenyl moiety optionally substituted with alkyl,halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl on the thienyl ring.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a cyclohexyl optionally substituted with alkyl, halo, alkenyl,alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl,aryl, or heteroaryl in the 2 or 3-position.

In another embodiment of the present invention, the active compound isof formula (I), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O; Y is CH₂;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a cyclohexyl moiety optionally substituted with alkyl, halo,alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl in the 4-position.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a thienyl moiety optionally substituted with alkyl, halo,alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl in the 2 or 3 position.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a thienyl moiety optionally substituted with alkyl, halo,alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl in the 4-position.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R¹ is a benzothiophenyl optionally substituted with alkyl, halo,alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl on the benzene ring.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a benzothiophenyl moiety optionally substituted with alkyl,halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl on the thienyl ring.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a cyclohexyl optionally substituted with alkyl, halo, alkenyl,alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl,aryl, or heteroaryl in the 2 or 3 position.

In another embodiment of the present invention, the active compound isof formula (II), its pharmaceutically acceptable salt or prodrugsthereof, wherein:

i) X is O;

ii) R¹ is fluorine or hydrogen;iii) R³ and R^(3′) are independently hydrogen or fluorine; R⁴ ishydrogen; andiv) R² is a cyclohexyl moiety optionally substituted with alkyl, halo,alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl,thioalkyl, aryl, or heteroaryl in the 4 position.

In one preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidine of the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-N⁴-(4-chlorobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-N⁴-(4-bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-5-fluoro-N⁴-(3-fluorobenzoyl)cytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-N⁴-(3-chlorobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-N⁴-(3-bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-5-fluoro-N⁴-(4-nitrobenzoyl)cytidine of the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-5-fluoro-N⁴-p-toluoylcytidine of the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-5-fluoro-N⁴-(m-toluoyl)cytidine of the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-N⁴-(4-ethylbenzoyl)-5-fluorocytidine of the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-5-fluoro-N⁴-(4-propylbenzoyl)cytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-N⁴-(4-tert-butylbenzoyl)-2′,3′-dideoxy-5-fluorocytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-2′,3′-dideoxy-5-fluoro-N⁴-(2-thiophenecarbonyl)cytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound is-D-N⁴-(benzo-[b]-thiophene-2-carbonyl)-2′,3′-dideoxy-5-fluorocytidine ofthe structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the active compound isβ-D-N⁴-(cyclohexane-carbonyl)-2′,3′-dideoxy-5-fluorocytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidine ofthe structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidineof the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the active compound isβ-D-N⁴-(4-chlorobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-N⁴-(4-bromobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-N⁴-p-anisoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(3-nitrobenzoyl)cytidineof the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-p-toluoylcytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the active compound isβ-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-m-toluoylcytidine of thestructure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-N⁴-(4-t-butylbenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In still another preferred embodiment, the active compound isβ-D-N⁴-cyclopentanecarbonyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound isβ-D-N⁴-(cyclohexanecarbonyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

or a pharmaceutically acceptable salt or prodrug thereof.

II. STEREOISOMERISM AND POLYMORPHISM

The compounds of the present invention have asymmetric centers and occuras racemates, racemic mixtures, individual diastereomers or enantiomers,with all isomeric forms being included in the present invention. Somecompounds may exhibit polymorphism. The present invention encompassesracemic, optically-active, polymorphic, or stereoisomeric form, ormixtures thereof, of a compound of the invention, which possess theuseful properties described herein. The optically active forms can beprepared by, for example, resolution of the racemic form byrecrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase or by enzymatic resolution.

Examples of methods to obtain optically active materials include atleast the following.

-   -   i) physical separation of crystals: a technique whereby        macroscopic crystals of the individual enantiomers are manually        separated. This technique can be used if crystals of the        separate enantiomers exist, i.e., the material is a        conglomerate, and the crystals are visually distinct;    -   ii) simultaneous crystallization: a technique whereby the        individual enantiomers are separately crystallized from a        solution of the racemate, possible only if the latter is a        conglomerate in the solid state;    -   iii) enzymatic resolutions: a technique whereby partial or        complete separation of a racemate by virtue of differing rates        of reaction for the enantiomers with an enzyme;    -   iv) enzymatic asymmetric synthesis: a synthetic technique        whereby at least one step of the synthesis uses an enzymatic        reaction to obtain an enantiomerically pure or enriched        synthetic precursor of the desired enantiomer;    -   v) chemical asymmetric synthesis: a synthetic technique whereby        the desired enantiomer is synthesized from an achiral precursor        under conditions that produce asymmetry (i.e., chirality) in the        product, which may be achieved using chiral catalysts or chiral        auxiliaries;    -   vi) diastereomer separations: a technique whereby a racemic        compound is reacted with an enantiomerically pure reagent (the        chiral auxiliary) that converts the individual enantiomers to        diastereomers. The resulting diastereomers are then separated by        chromatography or crystallization by virtue of their now more        distinct structural differences and the chiral auxiliary later        removed to obtain the desired enantiomer;    -   vii) first- and second-order asymmetric transformations: a        technique whereby diastereomers from the racemate equilibrate to        yield a preponderance in solution of the diastereomer from the        desired enantiomer or where preferential crystallization of the        diastereomer from the desired enantiomer perturbs the        equilibrium such that eventually in principle all the material        is converted to the crystalline diastereomer from the desired        enantiomer. The desired enantiomer is then released from the        diastereomer;    -   viii) kinetic resolutions: this technique refers to the        achievement of partial or complete resolution of a racemate (or        of a further resolution of a partially resolved compound) by        virtue of unequal reaction rates of the enantiomers with a        chiral, non-racemic reagent or catalyst under kinetic        conditions;    -   ix) enantiospecific synthesis from non-racemic precursors: a        synthetic technique whereby the desired enantiomer is obtained        from non-chiral starting materials and where the stereochemical        integrity is not or is only minimally compromised over the        course of the synthesis;    -   x) chiral liquid chromatography: a technique whereby the        enantiomers of a racemate are separated in a liquid mobile phase        by virtue of their differing interactions with a stationary        phase (including but not limited to via chiral HPLC). The        stationary phase can be made of chiral material or the mobile        phase can contain an additional chiral material to provoke the        differing interactions;    -   xi) chiral gas chromatography: a technique whereby the racemate        is volatilized and enantiomers are separated by virtue of their        differing interactions in the gaseous mobile phase with a column        containing a fixed non-racemic chiral adsorbent phase;    -   xii) extraction with chiral solvents: a technique whereby the        enantiomers are separated by virtue of preferential dissolution        of one enantiomer into a particular chiral solvent;    -   xiii) transport across chiral membranes: a technique whereby a        racemate is placed in contact with a thin membrane barrier. The        barrier typically separates two miscible fluids, one containing        the racemate, and a driving force such as concentration or        pressure differential causes preferential transport across the        membrane barrier. Separation occurs as a result of the        non-racemic chiral nature of the membrane that allows only one        enantiomer of the racemate to pass through.

Chiral chromatography, including but not limited to simulated moving bedchromatography, is used in one embodiment. A wide variety of chiralstationary phases are commercially available.

III. DEFINITIONS

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication. Thus, in a compound such as R″XYR″, wherein R″ is“independently carbon or nitrogen,” both R″ can be carbon, both R″ canbe nitrogen, or one R″ can be carbon and the other R″ nitrogen.

As used herein, the term “substantially free of” or “substantially inthe absence of” refers to a nucleoside composition that includes atleast 95% to 98% by weight, and even more preferably 99% to 100% byweight, of the designated enantiomer of that nucleoside. In a preferredembodiment, in the methods and compounds of this invention, thecompounds are substantially free of enantiomers.

Similarly, the term “isolated” refers to a nucleoside composition thatincludes at least 85 or 90% by weight, preferably 95% to 98% by weight,and even more preferably 99% to 100% by weight, of the nucleoside, theremainder comprising other chemical species or enantiomers.

The term “alkyl,” as used herein, unless otherwise specified, refers toa saturated straight, branched, or cyclic, primary, secondary, ortertiary hydrocarbon. The term includes both substituted andunsubstituted alkyl groups. The alkyl group may be optionallysubstituted with any moiety that does not otherwise interfere with thereaction or that provides an improvement in the process, including butnot limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl,aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino,dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester,carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine,thioester, thioether, acid halide, anhydride, oxime, hydrozine,carbamate, phosphonic acid, phosphonate, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene et al, Protective Groups in OrganicSynthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporatedby reference. Specifically included are CF₃ and CH₂CF₃

In the text, whenever the term C(alkyl range) is used, the termindependently includes each member of that class as if specifically andseparately set out. As a nonlimiting example, the term “C₁₋₂₂”independently represents each species that falls within the scope. Alkylgroups include, but are not limited to the radicals of methane, ethane,propane, cyclopropane, 2-methylpropane (isobutane), n-butane,2,2-dimethylpropane (neopentane), cytobutane, 1,1 dimethylcyclopropane,2-methylbutane, trans-1,2-dimethylcyclopropane, ethylcyclopropane,n-pentane, methylcyclobutane, cis-1,2-dimethylcyclopropane,spiropentane, cyclopentane, 2,2-dimethylbutane,1,1,2-trimethylcyclopropane, 2,3-dimethylbutane, 2-methylpentane,3-methylpentane, 1,2,3-trimethylcyclopropane, n-hexane,ethylcyclobutane, methylcyclopentane, 2,2dimethylpentane,2,4-dimethylpentane, cyclohexane, 2,2,3-trimethylbutane,3,3-dimethylpentane, 1,1-dimethylcyclopentane, 2,3-dimethylpentane,2-methylhexane, trans-1,3-dimethylcyclopentane,cis-1,3-dimethylcyclopentane, 3-methylhexane,trans-1,2-dimethylcyclopentane, 3-ethylpentane, quadricyclane(quadricyclo [2,2,1,0^(2.6), 0^(3.5)]heptane), n-heptane,2,2,4-trimethylpentane, cis-1,2-dimethylcyclopentane, methylcyclohexane,ethylcyclopentane, 1,1,3-trimethylcyclopentane, 2,2-dimethylhexane,2,5-dimethylhexane, 1,trans-2,cis-4-trimethylcyclopentane,2,4-dimethylhexane, 2,2,3-trimethylpentane,1,trans-2,cis-3-trimethylcyclopentane, 3,3-dimethylhexane,2,3,4-trimethylpentane, 1,1,2-trimethylcyclopentane,2,3,3-trimethylpentane, 2,3-dimethylhexane, 3-ethyl-2-methylpentane,1,cis-2,trans-4-trimethylcyclopentane,1,cis-2,trans-3-trimethylcyclopentane, 2-methylheptane, 4-methylheptane,3,4-dimethylhexane, 1,cis-2,cis-4-trimethylcyclopentane,3-ethyl-3-methylpentane, 3-ethylhexane, 3-methylheptane, cylotheptane(suberane), trans-1,4-dimethylcyclohexane, 1,1-dimethylcyclohexane,cis-1,3-dimethylcychohexane, trans-1-ethyl-3-methylcyclopentane,trans-1-ethyl-2-methylcyclopentane, cis-1-ethyl-3-methylcyclopentane,1-ethyl-1-methylcyclopentane, 2,2,4,4-tetramethylpentane,1,cis-2-cis-3-trimethylcyclopentane, trans-1,2-dimethylcyclohexane,2,2,5-trimethylhexane, trans-1,3-dimethylcyclohexane, n-octane,isopropylcyclopentane, 2,2,4-trimethylhexane,cis-1-ethyl-2-methylcyclopentane, cis-1,2-dimethylcyclohexane,2,4,4-trimethylhexane, n-propylcyclopentane, 2,3,5-trimethylhexane,ethylcyclohexane, 2,2-dimethylheptane, 2,2,3,4-tetramethylpentane,2,4-dimethylheptane, methylcycloheptane, 2,2,3-trimethylhexane,4-ethyl-2-methylhexane, 3-ethyl-2,2-dimethylpentane,4,4-dimethylheptane, 2,6-dimethylheptane, 2,5-dimethylheptane,3,5-dimethylheptane, bicyclo[4.2.0]octane, cis-bicyclo[3.3.0]octane,2,4-dimethyl-3-ethylpentane, 1,1,3-trimethylcyclohexane,3,3-dimethylheptane, 2,2,5,5-tetramethylhexane, 2,3,3-trimethylhexane,3-ethyl-2-methylhexane, trans-1,3,5-trimethylcyclohexane,2,3,4-trimethylhexane, cis-1,3,5-trimethylcyclohexane,trans-1,2,4-trimethylcyclohexane, 2,2,3,3-tetramethylpentane,4-ethyl-3-methylhexane, 3,3,4-trimethylhexane, 2,3-dimethylheptane,3,4-dimethylheptane, 3-ethyl-3-methylhexane, 4-ethylheptane,2,3,3,4-tetramethylpentane, 2,3-dimethyl-3-ethylpentane,trans-1,2,3-trimethylcyclohexane, 1-isopropyl-e-methylcyclopentane(pulegan), 4-methyloctane, 1-isopropyl-2-methylcyclopentane,3-ethylheptane, 2-methyloctane, cis-1,2,3-trimethylcyclohexane,3-methyloctane, 2,4,6-trimethylheptane, cis-1,2,4-trimethylcyclohexane,3,3-diethylpentane, 2,2-dimethyl-4-ethylhexane, 2,2,4-trimethylheptane,2,2,4,5-tetramethylhexane, 2,2,5-trimethylheptane,2,2,6-trimethylheptane, 2,2,3,5-tetramethylhexane, nopinane(7,7-dimethylbicyclo[3.1.1]heptane), trans-1-ethyl-r-methylcyclohexane,cycloctane, 1-ethyl-2-methylcyclohexane, n-nonane,1,3,3-trimethylbicyclo[2.2.1]heptane(fenchane),trans-1-ethyl-4-methylcyclohexane, cis-1,1,3,5-tetramethylcyclohexane,cis-1-ethyl-4-methylcyclohexane, 2,5,5-trimethylheptane,2,4,4-trimethylheptane, 2,3,3,5-tetramethylhexane,2,2,4,4-tetramethylhexane, isopropylcyclohexane,1,1,2,2-tetramethylcyclohexane, 2,2,3,4-tetramethylhexane,2,2-dimethyloctane, 3-ethyl-2,2,4-trimethylpentane,3,3,5-trimethylheptane, 2,3,5-trimethylheptane, 2,4-dimethyloctane,d,l-cis-1-ethyl-3-methylcyclohexane, d,l-2,5-dimethyloctane,1,1,3,5-tetramethylcyclohexane, n-butylcyclopentane,n-propylcyclohexane, 2,3,5-trimethylheptane, 2,5-dimethyl-3-ethylhexane,2,4,5-trimethylheptane, 2,4-dimethyl-3-isopropylpentane,2,2,3-trimethylheptane, 2,4-dimethyl-4-ethylhexane,2,2-dimethyl-3-ethylhexane, 2,2,3,4,4-pentamethylpentane,1,1,3,4-tetramethylcyclohexane, 5-ethyl-2-methylheptane,2,7-dimethyloctane, 3,6-dimethyloctane, 3,5-dimethyloctane,4-isopropylheptane, 2,3,3-trimethylheptane, 4-ethyl-2-methylheptane,2,6-dimethyloctane, 2,2,3,3-tetramethylhexane,trans-1-isopropyl-4-methylcyclohexane(p-menthane), 4,4-dimethyloctane,2,3,4,5-tetramethylhexane, 5-ethyl-e-methylheptane, 3,3-dimethyloctane,4,5-dimethyloctane, 3,4-diethylhexane, 4-propylheptane,1,1,4-trimethylcycloheptane (eucarvane),trans-1,2,3,5-tetramethylcyclohexane, 2,3,4,4-tetramethylhexane,2,3,4-trimethylheptane, 3-isopropyl-2-methylhexane,2,2,7-trimethylbicyclo[2.2.1]heptane(a-frenchane), 3-methylheptane,2,4-dimethyl-3-ethylhexane, 3,4,4-trimethylheptane,3,3,4-trimethylheptane, 3,4,5-trimethylheptane,2,3-dimemthyl-4-ethylhexane, 1-methyl-e-propylcyclohexane,2,3-dimethyloctane, d,l-pinane, 2,3,3,4-tetramethylhexane,3,3-dimethyl-4-ethylhexane, 5-methylnonane, 4-methylnonane,3-ethyl-2-methylheptane, 3,4-dimethyloctane, d-a-pinane,d,l-1-isopropyl-3-methylcyclohexane(d,l-m-menthane),2,2,3,3,4-pentamethylpentane, trans-1,2,4,5-tetramethylcyclohexane,3,3-diethylhexane, 2-methylnonane, d-1-isopropyl-3-methylcyclohexane(d-m-menthane), 3-ethyl-4-methylheptane, 4-ethyl-3-methylheptane,4-ethyl-4-methylheptane, 1-β-pinane, 3-methylnonane, 3-ethyloctane,4-ethyloctane, 3-ethyl-2,2,3-trimethylpentane,l-1-isopropyl-3-methylcyclohexane(1-m-menthane)cis-1-isopropyl-4-methylcyclohexane (cis-p-menthane),cis-1,2,3,5-tetramethylcyclohexane, 2,3-dimethyl-3-ethylhexane,1-isopropyl-4-methylcyclohexane (p-menthane),3,4-dimethyl-3-ethylhexane, 3,3,4,4-tetramethylhexane, cyclononane,1-isopropyl-2-methylcyclohexane (o-menthane),cis-1,2,4,5-tetramethylcyclohexane, 1-methyl-1-propylcyclohexane,n-decane, 1-methyl-4-propylcyclohexane, 1-methyl-2-propylcyclohexane,n-pentrylcyclopentane, n-butylcyclohexane, trans-decahydronaphthalene(trans-decalin), isoamylcyclohexane, cis-decahydronaphthalene(cis-decalin), n-undecane (n-hendecane), cyclodecane,n-pentylcyclohexane, n-hexylcyclopentane,9-methyl-trans-decahydronaphthalene,1,10-dimethyl-trans-decahydronaphthalene,9-methyl-cis-decahydronaphthalene, n-dodecane,1,10-dimethyl-cis-decahydronaphthalene, n-hexycyclohexane,n-heptylcyclopentane, 9-ethyl-trans-decahydronaphthalene,9-ethyl-cis-decahydronaphthalene, 1-methyl-trans-decahydronaphthalene,n-tridecane, bicyclohexyl, n-octylcyclopentane, n-heptylcyclohexane,n-tetradecane, n-nonylcyclopentane, n-octylcyclohexane, n-pentadecane,n-decyclopentane, n-nonylcyclohexane, n-undecylcyclopentane(n-hendecylcyclopentane), n-decylcyclohexane, 2-methylheptadecane,n-dodecylcyclopentane, n-undecylcyclohexane (n-hendecylcyclohexane),n-tridecylcyclopentane, n-dodecylcyclohexane, n-tetradecylcyclopentane,pentadecyclcyclopentane, n-hexadecane (cetane), tridecylcyclohexane,hexadeclcyclopentane, n-heptadecane, tetradecylcyclohexane,heptadecylcyclopentane, n-octadecane, pentadecylcyclohexane,octadecylcyclopentane, n-nonadecane, hexadecylcyclohexane,nonadecylcyclopentane, n-eicosane, heptadecylcyclohexane,eicosylcyclopentane, n-heneicosane, octadecylcyclohexane,heneicosylcyclopentane, n-docosane, docosylcyclopentane,nonadecylcyclohexane, n-tricosane, eicosylcyclohexane,tricosylcyclopentane, n-tetracosane, tetracosylcyclopentane,heneicosylcyclohexane, n-pentacosane, pentacosylcyclopentane,docosylcyclohexane, hexacosylcyclopentane, notricyclene(tricyclo[2.2.1.0^(2.6)]heptane), n-hexacosane, cyclohexadecane,tricosylcyclohexane, heptacosylcyclopentane, n-heptacosane,tetracosylcyclohexane, cyclopentadecane, octacosylcyclopentane,n-octacosane, pentacosylcyclohexane, nonacosylcyclopentane,n-nonacosane, hexacosylcyclohexane, triacontylcyclopentane,d,l-isobornane(2,2,3-trimethylbicyclo[2.2.2]heptane), n-triacontane,heptacosylcyclohexane, hentriacontylcyclopentane, n-hentriacontane,octacosylcyclohexane, dotriacontylcyclopentane, n-dotriacontane(bicetyl), noncosylcyclohexane, tritriacontylcyclopentane,tritriacontane, triacontylcyclohexane, tetratriacontylcyclopentane,tetratriacontane, 28-methylnonacosane, hentriacontylcyclohexane,pentatriacontylcyclopentane, pentatriacontane, dotriacontylcyclohexane,hexatriacontylcyclopentane, hexatriacontane, tritriacontylcyclohexane,heptatriacontane, tetratriacontylcyclohexane, octatriacontane,pentatriacontylcyclohexane, nonatriacontane, hexatriacontylcyclohexane,tetracontane, norbornane (bicyclo[2.2.1]heptane],2,2,3,3-tetramethylbutane, bornane (camphane), and adamantane. It isunderstood to those of ordinary skill in the art that the relevant alkylradical is named by replacing the suffix “-ane” with the suffix “-yl”.

The term “alkenyl” refers to an unsaturated, hydrocarbon radical, linearor branched, in so much as it contains one or more double bonds. Thealkenyl group disclosed herein can be optionally substituted with anymoiety that does not adversely affect the reaction process, includingbut not limited to but not limited to alkyl, halo, haloalkyl, hydroxyl,carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino,dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester,carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine,thioester, thioether, acid halide, anhydride, oxime, hydrozine,carbamate, phosphonic acid or phosphonate, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene et al., Protective Groups in OrganicSynthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporatedby reference. Non-limiting examples of alkenyl groups include methylene,ethylene, methylethylene, isopropylidene, 1,2-ethane-diyl,1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl,and 1,4-butane-diyl.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbonradical, linear or branched, in so much as it contains one or moretriple bonds. The alkynyl group may be optionally substituted with anymoiety that does not adversely affect the reaction process, includingbut not limited to but not limited to hydroxyl, halo (F, Cl, Br, I),perfluoro alkyl including but not limited to trifluoromethyl, amino,alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, acyl, amido,carboxamido, carboxylate, thiol, alkylthio, azido, sulfonic acid,sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected,or protected as necessary, as known to those skilled in the art, forexample, as taught in Greene et al., Protective Groups in OrganicSynthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporatedby reference. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl,pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl,hexyn-2-yl, and hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals.

The term “alkylamino” or “arylamino” refers to an amino group that hasone or two alkyl or aryl substituents, respectively.

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. Non-limitingexamples of aryl include phenyl, biphenyl, or naphthyl, or the followingaromatic group that remains after the removal of a hydrogen from thearomatic ring: benzene, toluene, ethylbenzene, 1,4-xylene, 1,3-xylene,1,2-xylene, isopropylbenzene (cumene), n-propylbenzene,1-ethyl-3-methylbenzene (m-ethyltoluene), 1-ethyl-4-methylbenzene(p-ethyltoluene), 1,3,5-trimethylbenzene (mesitylene),1-ethyl-2-methylbenzene (o-ethyltoluene), tert-butylbenzene,1,2,4-trimethylbenzene (pseudodocumene), isobutylbenzene,sec-butylbenzene, 3-isopropyl-methylbenzene (3-isopropyltoluene;m-cymene), 1,2,3-trimethylbenzene (hemimellitene),trans-propenylbenzene, indane, 4-isopropyl-1-methylbenzene(4-isopropyltoluene; 4-cymene), 2-isopropyl-methylbenzene(2-isopropyltoluene; 2-cymene), 1,3-diethbenzene, 1methyl-3-proplybenzene (m-propyltoluene), indene, n-butylbenzene,1-methyl-4-propylbenzene (p-propyltoluene), 1,2-diethylbenzene,1,4-diethylbenzene, 1,3-dimethyl-5-ethylbenzene,1-methyl-2-propylbenzene (o-propyltoluene), 2,2-dimethyl-1-phenylpropane(neopentylbenzene), 1,4-dimethyl-2-ethylbenzene, 2-methylindane,3-methyl-2-phenylbutane, 1-methylindane, 1,3-dimethyl-4-ethylbenzene,3-tert-butyl-menthylbenzene, (3-tert-butyltoluene),1,2-dimethyl-4-ethylbenzene, 1,3-dimethyl-2-ethylbenzene,3-phenylpentane, 1-ethyl-3-isopropylbenzene, 2-methyl-2-phenylbutane,4-tert-butyl 1-methylbenzene (4-tert-butyltoluene),1-ethyl-2-isopropylbenzene, 2-phenylpentane, 1,2-dimethyl-3-ethybenzene,3-sec-butyl-1-methylbenzene, (3-sec-butylotoluene),3-isobutyl-1-methylbenzene, (3-isobutyltoluene),d-2-methyl-1-phenylbutane, 1,3-dimethyl-5-isopropyl-benzene,2-phenyl-cis-2-butene, 4-isobutyl-methylblenzene (p-isobutyltoluene),2-sec-butyl-1-methylbenzene (2-sec-butyltoluene),2-isobutyl-1-methylblenzene (o-isobutyltoluene),1,4-dimethyl-2-isopropyl-benzene, 1-ethyl-4-isopropylbenzene,d,l-2-methyl-1-phenylbutane, 1,2,3,5-tetramethylbenzene (isodurene),3-methyl-1-phenylbutane (isopentylbenzene),1,3-dimethyl-2-isopropylbenzene, 1,3-dimethyl-4-isopropylbenzene),3-methylindene, 4-sec-butyl-1-methylbenzene (p-sec-butyltoluene),2-tert-butyl-1-methylbenzene (2-tert-butyltoluene),3,5-diethyl-1-methylbenzene (3,5-diethyltoluene),2-butyl-1-methylbenzene (2 butyltoluene), 1-ethyl-3-propylbenzene,1,2-dimethyl-4-isopropylbenzene, 1,2-dimethyl-3-isopropylbenzene,1-ethyl-2-propylbenzene, 1,3-di-isopropyllbenzene, 1,2-diethyl-4-methylbenzene, 1,2-di-isopropylbenzene, 1,4-dimethyl-2-proplybenzene,1,2,3,4-tetramethylbenzene (prehnitene), 1-ethyl-4-propylbenzene,3-butyl-1′-methlybenzene (m-butyltoluene), 2,4-diethyl-1′-methylbenzene(2,4-diethyltoluene), n-pentylbenzene, 3-methyl-3-phenylpentane,1,3-dimethyl-5-tert-butylbenzene, 1,3-dimethyl-4-propylbenzene,1,2-diethyl-3-methylbenzene, 4-butyl-1-methylbenzene, 4-butyl-1-methylbenzene, 1,2,3,4-tetrahydronaphthalene, 1,3-diethyl-2-propylbenzene,2,6-diethyl-1-methyl benzene, 1,2-dimethyl-4-propylbenzene,1,3-dimethyl-5-propylbenzene, 2-methyl-3-phenylpentane,4-teri-butyl-1,3-dimethylbenzene, 1,4-di-isopropylbenzene,1,2-dimethyl-3-propylbenzene, 1-teri-butyl-4-ethylbenzene,d,l-3-phenylhexane, 2-ethyl)-1,3,5-trimethyl-benzene,3-ethyly-4-isopropyl-1-methylbenzene, 5-ethyl-1,2,4-trimethylbenzene,6-ethyl-1-2,4-trimethylbenzene, 2-phenylhexane,2-methyl-1-phenylpentane, 4-isopropyl-1-propylbenzene,1,3-dipropylbenzene, 5-ethyl-1,2,3-trimethylbenzene,1,2,4-triethylbenzene, 1,3,5-triethylbenzene,2-methyl-1,2,3,4-tetrahydronaphthalene,1-methyl-1,2,3,4-tetrahydronaphthalene, 4-ethyl-1,2,3-trimethylbenzene,1,4-dipropylbenzene, 3-methyl-1-phenylpentane,2-propyl-1,3,5-trimethylbenzene,1,1-dimethyl-1,2,3,4-tetrahydronaphthalene,3-tert-butyl-1-isopropylbenzene, 1-methyl-3-pentylbenzene,4-tert-butyl-1-isopropylbenzene, 2-methyl-2-phenylhexane,2,4-di-isopropyl-1-methylbenzene, 3-methyl-3-phenylhexane,n-hexylbenzene, 3-phenylheptane, 2,6-di-isopropyl-1-methylbenzene,5-propyl-1,2,4-trimethylbenzene, 6-methyl-1,2,3,4-tetrahydronaphthalene,2,2-dimethyl-1,2,3,4-tetrahydronaphthalene, 2-phenylheptane,5-methyl-1,2,3,4-tetrahydronaphthalene,2-ethyl-1,2,3,4-tetrahydronaphthalene, cyclohexylbenzene,1-ethyl-1,2,3,4-tetrahydronaphthalene,2,5-dimethyl-1,2,3,4-tetrahydronaphthalene,2,8-dimethyl-1,2,3,4-tetrahydronaphthalene,2,7-dimethyl-1,2,3,4-tetrahydronaphthalene,2,6-dimethyl-1,2,3,4-tetrahydronaphthalene, 1,4-di-sec-butylbenzene,1,5-dimethyl-1,2,3,4-tetrahydronaphthalene, 3-ethyl-3-phenylhexane,6-ethyl-1,2,3,4-tetrahydronaphthalene, 2-methyl-1-phenyl-1-butene,5-ethyl-1,2,3,4-tetrahydronaphthalene, n-heptylbenzene,1-methylnaphthalene, 5,6-dimethyl-1,2,3,4-tetrahydronaphthalene,6,7-dimethyl-1,2,3,4-tetrahydronaphthalene,5,7-dimethyl-1,2,3,4-tetrahydronaphthalene, 2-ethylnaphthalene,1-7-dimethylnaphthalene, 1,6-dimethylnaphthalene,1,3-dimethylnaphthalene, n-octylbenzene, 1-allylnaphthalene,1-isopropylnaphthalene, 1,4-dimethylnaphthalene, 1,1-diphenylethane,2-isopropylnaphthalene, 2-propylnaphthalene, 1-propylnaphthalene,1,3,7-trimethylnaphthalene, 1-isopropyl-7-methylnaphthalene,n-nonylbenzene, 2-butylnaphthalene, 2-tert-butylnaphthalene,1-tert-butylnaphthalene, 1-butylnaphthalene, 4,5-benzindane,n-decylbenzene, 1-pentylnaphthalene, 2-pentylnaphthalene,n-undecylbenzene, 1-hexylnaphthalene, 2-hexylnaphthalene,n-dodecylbenzene, 1-heptylnaphthalene, 2-heptylnaphthalene,tridecylbenzene, 1-octylnaphthalene, 2-octylnaphthalene,1-nonylnaphthalene, 2-nonylnaphthalene, 1-decylnaphthalene,1,2,6-trimethylnaphthalene, diphenylmethane, 1,2,3-trimethylnaphthalene,1,6,7-trimethylnaphthalene, 2-isopropylazulene,1,4-dimethyl-7-isopropylazulene, 2,6-dimethylphenanthrene,1,2,5-trimethylnaphthalene, 1-propylphenanthrene, 5-isopropylazulene,5-isopropylazulene, 2-propylphenanthrene, 2-methylnaphthalene,1-ethyl-5-methylnaphthalene, 9-isopropylnaphthalene, 6-isopropylazulene,2-ethyl-6-methylnaphthalene, 2-isopropylphenanthrene,6-isopropyl-1-methylphenanthrene, 2-ethylazulene,2,5,-dimethylphenanthrene, 1,3,5-trimethylnaphthalene,3-ethyl-6-methylphenanthrene, 2-methylazulene,1,3,8-trimethylnaphthalene, 4-methylphenanthrene,1,4-dimethylphenanthrene, bibenzyl, methylenefluorene,3,5-dimethylphenanthrene, 1,3-dimethylazulene,7-methyl-3,4-benzphenanthrene, pentamethylbenzene,1,2,4-trimethylnaphthalene, 3,3-dimethylstilbene,1,4,5,7-tetramethylnaphthalene, 1,2,4,8-tetramethylnaphthalene,2,9-dimethylphenanthrene, 1,5-dimethylphenanthrene, 2-benzylnaphthalene,1-benzylnaphthalene, 1-benzylnaphthalene, 1,2-dimethylazulene,9-propylphenanthrene, 1,7-dimethyl-4-isopropylnaphthalene,3-methylphenanthrene, 3,4-dimethylphenanthrene, 1-ethylphenanthrene,sym-diphenylacetylene, 9-ethylphenanthrene, 1,4,5-trimethylnaphthalene,4-methylfluorene, 1,4,6,7-tretramethylnaphthalene,1,2,3-trimethylphenanthrene, 1,8-dimethylnaphthalene,8-methyl-3,4-benzphenanthrene, 2-ethylphenanthrene,3,4-benzphenanthrene, 1,3,7-trimethylphenanthrene,4-isopropyl-1-methylphenanthrene, 4,8-dimethylazulene, biphenyl,2-methyl-3,4-benzphenanthrene, 3-methylpyrene,1,4,7-trimethylphenanthrene, 1,4-dimethylanthracene,4,9-dimethyl-1,2-benzanthracene, benzalfluorene,1,3-dimethylphenanthrene, 1-methyl-3,4-benzphenanthrene,3-isopropyl-1-methylphenanthrene, 1,2-binaphthyl,2,3-dimethylphenanthrene, 1-ethyl-2-methylphenanthrene,1,5-dimethylnaphthalene, 6-methyl-3,4-benzphenanthrene, naphthalene,1,3,6,8-tetramethylnaphthalene, 1-ethyl-7methylphenanthrene,9-methylanthracene, 1-isopropyl-7-methylphenanthrene, 6-methylazulene,1,3-dimethylanthracene, 2,2-dimethylstilbene, 1-methylanthracene,1,7-dimethylphenanthrene, 1,6-diphenylnaphthalene,1,6-dimethylphenanthrene, 1,9-dimethylphenanthrene,9-methylphenanthrene, 1,2,10-trimethylanthracene,7-ethyl-1-methylphenanthrene, triphenylmethane,5-isopropylnaphthanthracene, 3,9-dimethyl-1,2-benzanthracene,5,6-benzindane, 12-isopropylnaphthanthracene, acenaphthene,2,7-dimethylnaphthalene, 7-isopropyl-1-methylfluorene, azulene, retene,phenanthrene, 2,7-dimethfylphenanthrene, 2,3,6-trimethfylnaphthalene,2-phenylnaphthalene, 1,2,3,4-tetrahydroanthracene,2,3-dimethylnaphthalene, ethylidenefluorene, 1,7-dimethylfuorene,1,1-dinaphthylmethane, fluoranthrene, 2,6-dimethylnaphthalene,2,4-dimethylphenanthrene, fluorene, 4,10-dimethyl-1,2-benzanthracene,4h-cyclopenta(def)phenanthrene, 1,3,8-trimethylphenanthrene,11-methylnaphthanthracene, 5-methylchrysene,1,2,5,6-tetramethylnaphthalene, cyclohept(fg)acenaphthene,1,2,7-trimethylphenanthrene, 1,10-dimethyl-1,2-dibenzanthracene,9,10-dimethyl-1,2-benzanthracene, benz(bc)aceanthrylene,1-methylphenanthrene, 1,6,7-trimethylphenanthrene, 1,1-diacenaphthene,trans-stilbene, 3,4-benzfluororene, 9-isopropylnaphthanthracene,6-methylnaphthanthracene, 5,8-dimethyl-1,2-bezanthracene,8-isopropylnaphthanthracene, 1,4,5,8-tetramethylnaphthalene,12-methylnaphthanthracene, 2-methyl-1,2-benzpyrene,1,5-dimethylanthracene, 7-methylnaphthanthracene,3,6-dimethylphenanthrene, 5-methyl-3,4-benzphenanthrene,1,4-dimethylchrysene, 1,2-dimethylphenanthrene,8,10-dimethyl-1,2-benzanthracene, 1,2,8-trimethylphenanthrene,3-methyl-1,2-benzpyrene, 9-methyl-1,2-benzpyrene, 9-phenylfluorene,2-methylnaphthanthracene, pyrene, 9-methylnaphthanthracene,4-methylchrysene, trans-trans-1,4-diphenyl-1,3-butadiene,cinnamalfluorene, 5-methylnaphthanthracene, 1,2-benzanthracene,8-methylnaphthanthracene, 1,1-binaphthyl, di-1-naphthastibene,6-methylchrysene, 3-methylnaphthanthracene,2,6-dimethyl-1,2-benzanthracene, cyclopentadienophenanthrene,10,11-benzfluoranthene, hexamethylbenzene, 3-methylchrysene,cholanthrene, 6-methyl-1,2-benzpyrene, 6,7-dimethyl-1,2-benzanthracene,1,2-benzpyrene, 5,10-dimethyl-1,2-benzanthracene, 4,5-benzpyrene,9,10-dimethylanthracene, 10-methylnaphthanthracene,5,6-dimethyl-1,2-benzanthracene, 2,2-binaphthyl, 1,2-benfluorene,1,8-dimethylphenanthrene, 8-methyl-1,2-benzpyrene, bifluorenylidene,1,2,7,8-dibenzanthracene, 4-methylnaphthanthracene,1,2,3,4-dibenzanthracene, di-2-fluorenylmethane, 2,3-benzfluorene,5-methyl-1,2-benzpyrene, anthracene, 11,12-benzfluoranthene,4-methyl-1,2-benzpyrene, 2,8-dimethylchrysene, 2-methylchrysene,6,12-dimethylchrysene, 1,2-benzphenanthrene, di-2-naphthastilbene,1-methylchrysene, 2,3,6,7-dibenzphenanthrene,2,3,5,6-dibenzphenanthrene, 1,2,5,6-dibenzanthracene, perylene, picene,1,2,3,4,5,6,7,8-tetrabenzanthracene, and coronene. The term arylincludes both substituted and unsubstituted moieties. The aryl group maybe optionally substituted with any moiety that does not adversely affectthe process, including but not limited to but not limited to halo,haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxylderivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy,nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl,sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl,phosphoryl, phosphine, thioester, thioether, acid halide, anhydride,oxime, hydrozine, carbamate, phosphonic acid, phosphonate, or any otherviable functional group that does not inhibit the pharmacologicalactivity of this compound, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene et al., Protective Groups in Organic Synthesis, John Wiley &Sons, Second Edition, 1991, hereby incorporated by reference.Non-limiting examples of substituted aryl include heteroarylamino,N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, heteroaralkoxy,arylamino, aralkylamino, arylthio, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,hydroxyaralkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl,aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partiallysaturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl,arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl,carboaralkoxy. The terms “alkaryl” or “alkylaryl” refer to an alkylgroup with an aryl substituent. The terms “aralkyl” or “arylalkyl” referto an aryl group with an alkyl substituent.

The term “halo,” as used herein, includes chloro, bromo, iodo andfluoro.

The term “acyl” refers to a carboxylic acid ester in which thenon-carbonyl moiety of the ester group is selected from straight,branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including but notlimited to methoxymethyl, aralkyl including but not limited to benzyl,aryloxyalkyl such as phenoxymethyl, aryl including but not limited tophenyl optionally substituted with halogen (F, Cl, Br, I), alkyl(including but not limited to C₁, C₂, C₃, and C₄) or alkoxy (includingbut not limited to C₁, C₂, C₃, and C₄), sulfonate esters such as alkylor aralkyl sulphonyl including but not limited to methanesulfonyl, themono, di or triphosphate ester, trityl or monomethoxytrityl, substitutedbenzyl, trialkylsilyl (e.g., dimethyl-t-butylsilyl) ordiphenylmethylsilyl. Aryl groups in the esters optimally comprise aphenyl group. The term “lower acyl” refers to an acyl group in which thenon-carbonyl moiety is lower alkyl.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branchedoxy-containing radicals having alkyl moieties, such as methoxy radical.The term “alkoxyalkyl” also embraces alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals. The “alkoxy” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, andfluoropropoxy.

The term “alkylamino” denotes “monoalkylamino” and “dialkylamino”containing one or two alkyl radicals, respectively, attached to an aminoradical. The terms arylamino denotes “monoarylamino” and “diarylamino”containing one or two aryl radicals, respectively, attached to an aminoradical. The term “aralkylamino”, embraces aralkyl radicals attached toan amino radical. The term aralkylamino denotes “monoaralkylamino” and“diaralkylamino” containing one or two aralkyl radicals, respectively,attached to an amino radical. The term aralkylamino further denotes“monoaralkyl monoalkylamino” containing one aralkyl radical and onealkyl radical attached to an amino radical.

The term “heteroatom,” as used herein, refers to oxygen, sulfur,nitrogen and phosphorus.

The terms “heteroaryl” or “heteroaromatic,” as used herein, refer to anaromatic that includes at least one sulfur, oxygen, nitrogen orphosphorus in the aromatic ring.

The term “heterocyclic” refers to a nonaromatic cyclic group whereinthere is at least one heteroatom, such as oxygen, sulfur, nitrogen, orphosphorus in the ring.

Nonlimiting examples of heteroaryl and heterocyclic groups includefuryl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl,isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl,isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl,cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan,pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole,1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine orpyridazine, and pteridinyl, aziridines, thiazole, isothiazole,1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine,oxaziranes, phenazine, phenothiazine, morpholinyl, pyrazolyl,pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl,pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl,imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine,N⁶-alkylpurines, N⁶-benzylpurine, N⁶-halopurine, N⁶-vinypurine,N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine,N⁶-thioalkyl purine, thymine, cytosine, 6-azapyrimidine,2-mercaptopyrmidine, uracil, N⁵-alkylpyrimidines, N⁵-benzylpyrimidines,N⁵-halopyrimidines, N⁵-vinylpyrimidine, N⁵-acetylenic pyrimidine,N⁵-acyl pyrimidine, N⁵-hydroxyalkyl purine, and N⁶-thioalkyl purine, andisoxazolyl. The heteroaromatic group can be optionally substituted asdescribed above for, aryl. The heterocyclic or heteroaromatic group canbe optionally substituted with one or more substituent selected fromhalogen (F, Cl, Br, I), haloalkyl, alkyl, alkoxy, hydroxy, carboxylderivatives, amido, amino, alkylamino, dialkylamino. The heteroaromaticcan be partially or totally hydrogenated as desired. As a nonlimitingexample, dihydropyridine can be used in place of pyridine. Functionaloxygen and nitrogen groups on the heterocyclic or heteroaryl group canbe protected as necessary or desired. Suitable protecting groups arewell known to those skilled in the art, and include trimethylsilyl,dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl,trityl or substituted trityl, alkyl groups, acyl groups such as acetyland propionyl, methanesulfonyl, and p-toluenelsulfonyl. The heterocyclicor heteroaromatic group can be substituted with any moiety that does notadversely affect the reaction, including but not limited to but notlimited to those described above for aryl.

The term “host,” as used herein, refers to a unicellular ormulticellular organism in which the virus can replicate, including butnot limited to cell lines and animals, and preferably a human.Alternatively, the host can be carrying a part of the viral genome,whose replication or function can be altered by the compounds of thepresent invention. The term host specifically refers to infected cells,cells transfected with all or part of the viral genome and animals, inparticular, primates (including but not limited to chimpanzees) andhumans. In most animal applications of the present invention, the hostis a human patient. Veterinary applications, in certain indications,however, are clearly anticipated by the present invention (such aschimpanzees).

The term “pharmaceutically acceptable salt or prodrug” is usedthroughout the specification to describe any pharmaceutically acceptableform (such as an ester, phosphate ester, salt of an ester or a relatedgroup) of a nucleoside compound which, upon administration to a patient,provides the nucleoside compound. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids. Suitable salts include those derived fromalkali metals such as potassium and sodium, alkaline earth metals suchas calcium and magnesium, among numerous other acids well known in thepharmaceutical art. Pharmaceutically acceptable prodrugs refer to acompound that is metabolized, for example hydrolyzed or oxidized, in thehost to form the compound of the present invention. Typical examples ofprodrugs include compounds that have biologically labile protectinggroups on a functional moiety of the active compound. Prodrugs includecompounds that can be oxidized, reduced, aminated, deaminated,hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated,dealkylated, acylated, deacylated, phosphorylated, dephosphorylated toproduce the active compound. The compounds of this invention possessantiviral activity against Flaviviridae, or are metabolized to acompound that exhibits such activity.

Prodrugs also include natural or unnatural amino acid esters of thedisclosed nucleosides (see, e.g., European Patent Specification No.99493, the text of which is incorporated by reference, which describesamino acid esters of acyclovir, specifically the glycine and alanineesters which show improved water-solubility compared with acycloviritself, and U.S. Pat. No. 4,957,924 (Beauchamp), which discloses thevaline ester of acyclovir, characterized by side-chain branchingadjacent to the α-carbon atom, which showed improved bioavailabilityafter oral administration compared with the alanine and glycine esters).A process for preparing such amino acid esters is disclosed in U.S. Pat.No. 4,957,924 (Beauchamp), the text of which is incorporated byreference. As an alternative to the use of valine itself, a functionalequivalent of the amino acid may be used (e.g., an acid halide such asthe acid chloride, or an acid anhydride). In such a case, to avoidundesirable side-reactions, it may be is advantageous to use anamino-protected derivative.

IV. NUCLEOTIDE SALT OR PRODRUG FORMULATIONS

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate. Examples ofpharmaceutically acceptable salts are organic acid addition salts formedwith acids, which form a physiological acceptable anion, for example,tosylate, methanesulfonate, acetate, citrate, malonate, tartarate,succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate.Suitable inorganic salts may also be formed, including but not limitedto, sulfate, nitrate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid, affording aphysiologically acceptable anion. Alkali metal (e.g., sodium, potassiumor lithium) or alkaline earth metal (e.g., calcium) salts of carboxylicacids can also be made.

Any of the nucleosides described herein can be administered as anucleotide prodrug to increase the activity, bioavailability, stabilityor otherwise alter the properties of the nucleoside. A number ofnucleotide prodrug ligands are known. In general, alkylation, acylationor other lipophilic modification of the mono, di or triphosphate of thenucleoside will increase the stability of the nucleotide. Examples ofsubstituent groups that can replace one or more hydrogens on thephosphate moiety are alkyl, aryl, steroids, carbohydrates, including butnot limited to sugars, 1,2-diacylglycerol and alcohols. Many aredescribed in R. Jones & N. Bischofberger, Antiviral Research, 27 (1995)1-17. Any of these can be used in combination with the disclosednucleosides to achieve a desired effect.

The active nucleoside can also be provided as a 5′-phosphoether lipid ora 5′-ether lipid, as disclosed in the following references, which areincorporated by reference: Kucera, L. S., N. Iyer, E. Leake, A. Raben,Modest E. K., D. L. W., and C. Piantadosi, “Novel membrane-interactiveether lipid analogs that inhibit infectious HIV-1 production and inducedefective virus formation,” AIDS Res. Hum. Retroviruses, 1990, 6,491-501; Piantadosi, C., J. Marasco C. J., S. L. Morris-Natschke, K. L.Meyer, F. Gumus, J. R. Surles, K. S. Ishaq, L. S. Kucera, N. Iyer, C.A.Wallen, S. Piantadosi, and E. J. Modest, “Synthesis and evaluation ofnovel ether lipid nucleoside conjugates for anti-HIV activity,” J. Med.Chem., 1991, 34, 1408-1414; Hosteller, K. Y., D. D. Richman, D. A.Carson, L. M. Stuhmiller, G. M. T. van Wijk, and H. van den Bosch,“Greatly enhanced inhibition of human immunodeficiency virus type Ireplication in CEM and HT4-6C cells by 3′-deoxythymidine diphosphatedimyristoylglycerol, a lipid prodrug of 3,-deoxythymidine,” Antimicrob.Agents Chemother., 1992, 36, 2025-2029; Hostetler, K. Y., L. M.Stuhmiller, H. B. Lenting, H. van den Bosch, and D. D. Richman,“Synthesis and antiretroviral activity of phospholipid analogs ofazidothymidine and other antiviral nucleosides.” J. Biol. Chem., 1990,265, 61127.

Nonlimiting examples of US patents that disclose suitable lipophilicsubstituents that can be covalently incorporated into the nucleoside,preferably at the 5′-OH position of the nucleoside or lipophilicpreparations, include U.S. Pat. Nos. 5,149,794 (Yatvin et al.);5,194,654 (Hostetler et al.), 5,223,263 (Hostetler et al.); 5,256,641(Yatvin et al.); 5,411,947 (Hostetler et al.); 5,463,092 (Hostetler etal.); 5,543,389 (Yatvin et al.); 5,543,390 (Yatvin et al.); 5,543,391(Yatvin et al.); and 5,554,728 (Basava et al.), all of which areincorporated by reference. Foreign patent applications that discloselipophilic substituents that can be attached to nucleosides of thepresent invention, or lipophilic preparations, include WO 89/02733, WO90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO96/15132, EP 0 350 287, EP 93917054.4, and WO 91/19721.

V. COMBINATION OR ALTERNATION THERAPY

In another embodiment for the treatment of HIV or HBV infection, theactive compound or its prodrug or salt can be administered incombination or alternation with another antiviral agent, such as anotheractive anti-HIV or anti-HBV agent, including but not limited to those ofthe formulae above, others listed below or known in the art. In general,in combination therapy, effective dosages of two or more agents areadministered together, whereas during alternation therapy, an effectivedosage of each agent is administered serially. The dosage will depend onabsorption, inactivation and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens and schedules should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions.

Nonlimiting examples of antiviral agents that can be used in combinationwith the compounds disclosed herein include those in the tables below.

Hepatitis B Therapies Drug Name Drug Class Company Intron A (interferonalfa-2b) interferon Schering-Plough Epivir-HBV (lamivudine; 3TC)nucleoside analogue GlaxoSmithKline Hepsera (Adefovir Dipivoxi)”nucleotide analogue Gilead Sciences Coviracil (emtricitabine; FTC)nucleoside analogue Triangle Pharmaceuticals Entecavir nucleosideanalogue Bristol-Myers Squibb Clevudine (L-FMAU) nucleoside analogueTriangle Pharmaceuticals ACH 126, 443 (L-Fd4C) nucleoside analogueAchillion Pharmaceuticals AM 365 nucleoside analogue Amrad Amdoxovir(formerly DAPD) nucleoside analogue Triangle Pharmaceuticals LdT(telbivudine) nucleoside analogue Idenix XTL 001 monoclonal antibody XTLBiopharm Theradigm Immune stimulant Epimmune Zadaxin (thymosin) Immunestimulant SciClone EHT 899 viral protein Enzo Biochem HBV DNA vaccineImmune stimulant PowderJect (UK) MCC 478 nucleoside analogue Eli LillyvalLdC (valtorcitabine) nucleoside analogue Idenix ICN 2001 nucleosideanalogue ICN Fluro L and D nucleosides nucleoside analogue PharmassetRacivir nucleoside analogue Pharmasset Robustaflavone nucleosideanalogue Advanced Life Sciences Penciclovir DXG HDP-P-acyclovir LM-019cCS-109 PS-019 PS-018 ara-AMP prodrugs HBV/MF59 Hammerhead ribozymesGlycosidase Inhibitors Pegylated Interferon Human Monoclonal AntibodiesFamciclovir

HIV Therapies: Protease Inhibitors (PIs) Brand Pharmaceutical NameGeneric Name Abbreviation Company Invirase ® saquinavir (Hard SQV (HGC)Hoffmann-La Roche Gel Cap) Fortovase ® saquinavir (Soft SQV (SGC)Hoffmann-La Roche Gel Cap) Norvir ® ritonavir RTV Abbott LaboratoriesCrixivan ® indinavir IDV Merck & Co. Viracept ® nelfinavir NFV PfizerAgenerase ® amprenavir APV GlaxoSmithKline Kaletra ® lopinavir + LPVAbbott Laboratories ritonavir fosamprenavir GlaxoSmithKline tipranavirTPV Boehringer Ingelheim atazanavir Bristol-Myers Squibb

HIV Therapies: Nucleoside/Nucleotide Reverse Transcriptase Inhibitors(NRTIs) Brand Pharmaceutical Name Generic Name Abbreviation CompanyRetrovir ® zidovudine AZT or ZDV GlaxoSmithKline Epivir ® lamivudine 3TCGlaxoSmithKline Combivir ® zidovudine + AZT + 3TC GlaxoSmithKlinelamivudine Trizivir ® abacavir + ABC + AZT + GlaxoSmithKlinezidovudine + 3TC lamivudine Ziagen ® abacavir ABC GlaxoSmithKlineHivid ® zalcitabine ddC Hoffmann-La Roche Videx ® didanosine: bufferedddI Bristol-Myers versions Squibb Videx ® EC didanosine: delayed- ddIBristol-Myers release capsules Squibb Zerit ® stavudine d4TBristol-Myers Squibb Viread ™ tenofovir disoproxil TDF or GileadSciences fumarate (DF) Bis(POC) PMPA Coviracil ™ emtricitabine FTCTriangle Pharmaceuticals amdoxovir DAPD Triangle Pharmaceuticals

HIV Therapies: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Brand Pharmaceutical Name Generic Name Abbreviation Company Viramune ®nevirapine NVP Boehringer Ingelheim Rescriptor ® delavirdine DLV PfizerSustiva ® efavirenz EFV Bristol-Myers Squibb (+)-calanolide A SarawakMedichem capravirine CPV Pfizer Bristol-Myers Squibb Tibotec-Virco GroupTibotec-Virco Group

HIV Therapies: Other Classes of Drugs Brand Pharmaceutical Name GenericName Abbreviation Company Viread ™ tenofovir disoproxil TDF or Bis(POC)Gilead Sciences fumarate (DF) PMPA Cellular Inhibitors Droxia ®hydroxyurea HU Bristol-Myers Squibb Entry Inhibitors (including FusionInhibitors) Fuzeon ™ enfuvirtide Trimeris Trimeris AnorMED, Inc.Progenics Pharmaceuticals

HIV Therapies: Immune-Based Therapies Brand Pharmaceutical Name GenericName Abbreviation Company Proleukin ® aldesleukin, or IL-2 ChironCorporation Interleukin-2 Remune ® HIV-1 The Immune Immunogen, orResponse Salk vaccine Corporation HollisEden Pharmaceuticals

HIV Therapies: Treatments for Side Effects Brand Pharmaceutical NameGeneric Name Side Effect Company Procrit ® epoetin alfa Anemia OrthoBiotech (erythropoietin) Serostim ® somatropin, or Lipodystrophy Seronohuman growth Laboratories hormone

In one embodiment, the compounds of the invention may be employedtogether with at least one other antiviral agent chosen from reversetranscriptase inhibitors, protease inhibitors, fusion inhibitors, entryinhibitors and polymerase inhibitors.

In addition, compounds according to the present invention can beadministered in combination or alternation with one or moreanti-retrovirus, anti-HBV, anti-HCV or anti-herpetic agent orinterferon, anti-cancer or antibacterial agents, including but notlimited to other compounds of the present invention. Certain compoundsaccording to the present invention may be effective for enhancing thebiological activity of certain agents according to the present inventionby reducing the metabolism, catabolism or inactivation of othercompounds and as such, are co-administered for this intended effect.

VI. PHARMACEUTICAL COMPOSITIONS

Host, including but not limited to humans, infected with a humanimmunodeficiency virus, a hepatitis virus, or a gene fragment thereof,can be treated by administering to the patient an effective amount ofthe active compound or a pharmaceutically acceptable prodrug or saltthereof in the presence of a pharmaceutically acceptable carrier ordiluent. The active materials can be administered by any appropriateroute, for example, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, in liquid or solid form.

A preferred dose of the compound for an HIV or HBV infection will be inthe range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of bodyweight per day, more generally 0.1 to about 100 mg per kilogram bodyweight of the recipient per day. The effective dosage range of thepharmaceutically acceptable salts and prodrugs can be calculated basedon the weight of the parent nucleoside to be delivered. If the salt orprodrug exhibits activity in itself, the effective dosage can beestimated as above using the weight of the salt or prodrug, or by othermeans known to those skilled in the art.

The compound is conveniently administered in unit any suitable dosageform, including but not limited to but not limited to one containing 7to 3000 mg, preferably 70 to 1400 mg of active ingredient per unitdosage form. An oral dosage of 50-1000 mg is usually convenient.

Ideally the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.2 to 70 μM,preferably about 1.0 to 10 μM. This may be achieved, for example, by theintravenous injection of a 0.1 to 5% solution of the active ingredient,optionally in saline, or administered as a bolus of the activeingredient.

The concentration of active compound in the drug composition will dependon absorption, inactivation and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcomposition. The active ingredient may be administered at once, or maybe divided into a number of smaller doses to be administered at varyingintervals of time.

A preferred mode of administration of the active compound is oral. Oralcompositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring. When the dosageunit form is a capsule, it can contain, in addition to material of theabove type, a liquid carrier such as a fatty oil. In addition, unitdosage forms can contain various other materials that modify thephysical form of the dosage unit, for example, coatings of sugar,shellac, or other enteric agents.

The compound can be administered as a component of an elixir,suspension, syrup, wafer, chewing gum or the like. A syrup may contain,in addition to the active compound(s), sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors.

The compound or a pharmaceutically acceptable prodrug or salts thereofcan also be mixed with other active materials that do not impair thedesired action, or with materials that supplement the desired action,such as antibiotics, antifungals, anti-inflammatories or otherantivirals, including but not limited to other nucleoside compounds.Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents, such as ethylenediaminetetraacetic acid; buffers, suchas acetates, citrates or phosphates, and agents for the adjustment oftonicity, such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including but notlimited to implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters and polylactic acid. For example, enterically coatedcompounds can be used to protect cleavage by stomach acid. Methods forpreparation of such formulations will be apparent to those skilled inthe art. Suitable materials can also be obtained commercially.

Liposomal suspensions (including but not limited to liposomes targetedto infected cells with monoclonal antibodies to viral antigens) are alsopreferred as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art, for example, asdescribed in U.S. Pat. No. 4,522,811 (incorporated by reference). Forexample, liposome formulations may be prepared by dissolving appropriatelipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoylphosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol)in an inorganic solvent that is then evaporated, leaving behind a thinfilm of dried lipid on the surface of the container. An aqueous solutionof the active compound or its monophosphate, diphosphate, and/ortriphosphate derivatives is then introduced into the container. Thecontainer is then swirled by hand to free lipid material from the sidesof the container and to disperse lipid aggregates, thereby forming theliposomal suspension.

VII. PROCESSES FOR THE PREPARATION OF ACTIVE COMPOUNDS

A method for the facile preparation of N⁴-acyl-substituted2′,3′-dideoxy-5-fluorocytidine and2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine nucleosides is alsoprovided. The method includes condensation of a 5′-O-silyl protected2′,3′-dideoxy-5-fluorocytidine or a 5′-O-silyl protected2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, with either a carboxylicacid chloride, or carboxylic acid anhydride, or a carboxylic acid,followed by desilylation. The other N⁴-acyl-substituted cytosinenucleosides can be synthesized using the similar approaches.

The N⁴-acyl-substituted 2′,3′-dideoxy-5-fluorocytidine and2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine nucleosides disclosedherein can be prepared as described in detail below, or by other assaysknown to those skilled in the art.

The present invention is further illustrated in the following examples.It will be understood by one of ordinary skill in the art that theseexamples are in no way limiting and that variations of detail can bemade without departing from the spirit and scope of the presentinvention.

EXAMPLES

Anhydrous solvents were purchased from Aldrich Chemical Company, Inc.(Milwaukee). Melting points (mp) were determined on an Electrothermaldigit melting point apparatus and are uncorrected. ¹H and ¹³C NMRspectra were taken on a Varian Unity Plus 400 spectrometer at roomtemperature and reported in ppm downfield from internaltetramethylsilane. Deuterium exchange, decoupling experiments or 2D-COSYwere performed to confirm proton assignments. Signal multiplicities arerepresented by s (singlet), d (doublet), dd (doublet of doublets), t(triplet), q (quadruplet), br (broad), bs (broad singlet), m(multiplet). All J-values are in Hz. Mass spectra were recorded on aJEOL JMS-SX/SX102A/E mass spectrometer. Elemental analyses wereperformed by Atlantic Microlab Inc. (Norcross, Ga.). Analytic TLC wasperformed on Whatman LK6F silica gel plates, and preparative TLC onWhatman PK5F silica gel plates. Column chromatography was carried out onSilica Gel (Fisher, S733-1) at atmospheric pressure.

Example 1 (S)-(+)-5-Oxo-2-tetrahydrofurancarboxylic Acid (2)

To a mixture of L-glutamic acid (1, 25 g, 170 mmol) in water (67 mL) andconc. HCl (35 mL) at 0° C. with stirring was added a solution of NaNO₂(17.5 g, 253.6 mmol) in water (37.5 mL) over a period of 4 h, and thenthe resulting clear solution was stirred at room temperature overnight.After removal of the solvent by evaporation in vacuo, the residue wastreated with EtOAC (80 mL) and filtered. The filtrate was dried overNa₂SO₄, and concentrated. The residue, after crystallization fromEtOAc/benzene/hexane, afforded the title compound 2 as a whitecrystalline solid (13.12 g, 59%). M.P. 71-73° C.; ¹H NMR (400 MHz,CD₃OD) δ 4.20 (m, 1H, CHO), 1.8-2.3 (m, 4H, CH₂CH₂).

Example 2 (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3H)-furanone (3)

To a solution of 2 (10 g, 76.85 mmol) in anhydrous THF (200 mL) at 0° C.was slowly added BH₃—SMe₂ (2 M solution in THF, 46.1 mL, 92.2 mmol) overa period of 10 min. The reaction solution was stirred at 0° C. for 3 hunder nitrogen, followed by the slow addition of anhydrous MeOH (20 mL).After removal of the solvent, the residue was purified by flashchromatography on silica gel eluting with CH₂Cl₂/MeOH (95:5) to give thetitle compound 3 as a colorless oil (8.41 g, 94%). ¹H NMR (CDCl₃) δ4.66-4.65 (m, 1H, H-5), 3.95-3.91 (m, 1H, CH₂OH), 3.72-3.65 (m, 1H,CH₂OH), 2.65-2.57 (m, 2H, H-3), 2.30-2.17 (m, 3H, H-4, OH).

Example 3(S)-5-[(tert-Butyldiphenylsilyl)hydroxymethyl]-dihydro-2(3H)-furanone(4)

To a solution of 3 (7.0 g, 60 mmol) and imidazole (9.19 g, 135 mmol) inanhydrous DMF (70 mL) was added tert-butyldiphenylsilyl chloride (18.14g, 66 mmol, 17.2 mL), and the solution was stirred at room temperatureunder a nitrogen atmosphere for 1 h. After removal of the solvent byevaporation, the residue was dissolved in CHCl₃, washed with water andbrine, dried (Na₂SO₄), filtered, and concentrated. After crystallizationfrom hexane, the oily residue gave the title compound 4 as a whitecrystalline solid (20.6 g, 97%). M.P. 76° C.; ¹H NMR (CDCl₃) δ 7.68-7.65(m, 4H, arom.), 7.47-7.39 (m, 6H, arom.), 4.63-4.61 (m, 1H, H-5),3.90-3.87 (dd, J=3 & 11 Hz, 1H, CH₂OH), 3.70-3.67 (dd, J=3 & 11 Hz, 1H,CH₂OH), 2.69-2.65 (m, 1H, H-3), 2.56-2.52 (m, 1H, H-3), 2.32-2.23 (m,2H, H-4), 1.06 (s, 9H, t-Bu).

Example 4(5S,3R)-5-[(tert-Butyldiphenylsilyl)hydroxymethyl]-dihydro-3-(phenylselenenyl)-2(3H)-furanone(5)

To a solution of 4 (5 g, 14.1 mmol) in anhydrous THF (50 mL) at −78° C.was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 15.8mL, 15.8 mmol) over a period of 10 min. After stirring at −78° C. for 1h, Me₃SiCl (1.918 g, 17.65 mmol) was added dropwise, and the reactionmixture was allowed to warm to room temperature. After being stirred atroom temperature for 30 min, the mixture was cooled to −78° C., and asolution of PhSeBr (5 g, 21.19 mmol) in anhydrous THF (25 mL) was addedrapidly. The mixture was diluted with ether (50 mL), washed with wateruntil the color of organic layer changed from dark brown to lightyellow, dried (Na₂SO₄), filtered, and evaporated. The resulting oilyresidue [containing 3R(α, 5) and 3S(β) isomers; TLC: hexane/EtOAc, 10:1;R_(f)=0.42 and 0.28, respectively] was purified by flash chromatographyon silica gel eluting with hexane/EtOAc (99:1 to 95:5) to give the titlecompound 5 as a light yellow oil (4.22 g, 59%). ¹H NMR (CDCl₃) δ7.69-7.60 (m, 6H, arom.), 7.46-7.30 (m, 9H, arom.), 4.37-4.34 (m, 1H, H-5), 4.12-4.08 (m, 1H, H-3), 3.86-3.82 (dd, J=3 & 11 Hz, 1H, CH₂OH),3.62-3.59 (dd, J=3 & 11 Hz, 1H, CH₂OH), 2.73-2.67 (m, 1H, H-4),2.32-2.28 (m, 1H, H-4), 1.02 (s, 9H, t-Bu).

Example 51-O-Acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-(phenylselenenyl)-α/β-D-erythro-pentofuranose(6)

To a stirred solution of 5 (13.68 g, 26.88 mmol) in anhydrous toluene(120 mL) at −78° C. was added diisobutylaluminum hydride (1 M solutionin toluene, 43 mL, 43 mmol), and the solution was stirred at −78° C. for2 h under an argon atmosphere. The reaction was quenched by addition ofanhydrous MeOH (10 mL), and the mixture was allowed to warm to roomtemperature. After stirring at room temperature for 30 min, EtOAc (50mL) and water (50 mL) were added. The resulting white precipitate wasfiltered, and the aqueous layer was extracted with EtOAc. The combinedorganic phase was washed with water and brine, dried (Na₂SO₄), filtered,and evaporated. The resulting oily residue was dissolved in anhydrousCH₂Cl₂ (60 mL), and cooled to 0° C. 4-Dimethylaminopyridine (DMAP, 5 mg)and pyridine (15 mL) were added, followed by Ac₂O (8.22 g, 80.64 mmol).The mixture was stirred at 0° C. for 30 min, then at room temperatureovernight. Evaporation of the solvent in vacuo afforded the titlecompound 6 as a clear yellow oil (13.45 g, 90%). This crude product wasused directly without further purification. ¹H NMR (CDCl₃) δ 7.69-7.55(m, 6H, arom.), 7.44-7.25 (m, 9H, arom.), 6.47-6.46 (d, H-1), 6.28 (s,H-1), 4.47-4.34 (m, 1H, H-4), 3.82-3.54 (m, 3H, H-5, H-2), 2.50-1.99 (m,2H, H-3), 2.12, 1.86 (2s, 3H, CH₃CO), 1.05, 1.96 (2s, 9H, t-Bu).

Example 6β-D-5′-O-(tert-Butyldiphenylsilyl)-2′,3′-dideoxy-5-fluoro-2′-(phenylselenenyl)-cytidine(7)

A suspension of 5-fluorocytosine (1.61 g, 12.5 mmol) and (NH₄)₂SO₄ (165mg, 1.25 mmol) in hexamethyldisilazane (20 mL) was heated at reflux for2 h under an argon atmosphere, and then evaporated to dryness in vacuo.To the residue was added a solution of 6 (5.53 g, 10.0 mmol) inanhydrous 1,2-dichloroethane (25 mL), and the mixture was cooled to 5°C. TMSOTf (2.0 mL, 11 mmol) was added, and the resulting solution wasstirred at 5° C. for 15 min under an argon atmosphere, then at roomtemperature for another 30 min. The solution was poured into a mixtureof EtOAc and saturated aqueous NaHCO₃ with stirring. The organic layerwas separated, washed with saturated NaHCO₃ solution, water, and brine,dried (Na₂SO₄), filtered, and concentrated. The residue was purified byflash chromatography on silica gel eluting with CH₂Cl₂/MeOH (99:1 to96:4) to give 7 (5.36 g, 86%) as a white solid. M.P. 163-164° C.; ¹H NMR(CDCl₃) δ 7.95 (d, J=6.4 Hz, 1H, H-6), 7.67-7.62 (m, 6H, arom.),7.47-7.25 (m, 9H, arom.), 6.90 (bs, 1H, NH), 6.15-6.14 (m, 1H, H-1′),5.40 (bs, 1H, NH), 4.32-4.30 (m, 1H, H-4′), 4.12-4.08 (m, 1H, H-5′a),3.84-3.83 (m, 1H, H-2′), 3.65 (dd, J=2.4 & 11.2 Hz, 1H, H-5′b),2.45-2.42, 2.01-1.98 (2m, 2H, H-3′), 1.08 (s, 9H, t-Bu); ¹³C NMR (CDCl₃)δ 157.0, 156.8, 153.3, 137.3, 135.6, 135.5, 135.4, 134.9, 132.6, 132.3,130.1, 130.0, 129.2, 128.3, 127.9, 127.4, 125.5, 125.2, 91.0, 80.2,64.8, 45.4, 32.3, 26.9, 19.2.

Example 7β-D-5′-O-(tert-Butyldiphenylsilyl)-2,3′-dideoxy-5-fluorocytidine (8)

A suspension of 7 (4.976 g, 8 mmol), Et₃B (1 M solution in hexane, 8.8mL, 8.8 mmol), and n-Bu₃SnH (3.23 mL, 12 mmol) in anhydrous benzene (40mL) was stirred at room temperature under an argon atmosphere for 5 h.After evaporation of the solvent, the residue was purified by flashchromatography on silica gel eluting with CH₂Cl₂/MeOH (99:1 to 96:4) togive the title compound 8 as a pale yellow foam (3.45 g, 92%). ¹H NMR(CDCl₃) δ 8.14 (d, J=6.4 Hz, 1H, H-6), 7.71-7.66 (m, 4H, arom.),7.49-7.38 (m, 6H, arom.), 6.04 (m, 1H, H-1′), 4.17-4.12 (m, 1H, H-4′),4.12-4.08 (m, 1H, H-5′a), 3.73-3.69 (m, 1H, H-5′b), 2.54-2.44, 2.18-2.09(2m, 2H, H-2′), 2.05-1.95, 1.89-1.82 (2m, 2H, H-3′), 1.10 (s, 9H, t-Bu).

Example 8β-D-5′-O-(tert-Butyldiphenylsilyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine(9)

To a solution of 7 (15.47 g, 24.87 mmol) in CH₂Cl₂ (150 mL) containing 5drops of pyridine at 0° C. was added a solution of H₂O₂ (15.5 mL of 30%solution) dropwise over a period of 15 min. After stirring at 0° C. for20 min, and at room temperature for 30 min, the reaction solution wasdiluted with CHCl₃ (200 mL), washed with H₂O, saturated NaHCO₃ solution,and H₂O, dried (Na₂SO₄), filtered, and concentrated. The residue, afterpurification by chromatography over silica gel eluted with CH₂Cl₂/MeOH(96:4), gave 9 as a pale yellow foam (9.907 g, 86%). M.P. 150-152° C.;¹H NMR (CDCl₃) δ 7.88 (d, J=6.4 Hz, 1H, H-6), 7.66-7.65 (m, 4H, arom.),7.47-7.37 (m, 6H, arom.), 7.00-6.99 (m, 1H, H-1′), 6.50 (bs, 1H, NH),6.12 (d, J=6.0 Hz, 1H, H-3′), 5.98 (d, J=4.8 Hz, 1H, H-2′), 5.35 (bs,1H, NH), 4.89 (bs, 1H, H-4′), 4.00 (dd, J=3.2 & 11.6 Hz, 1H, H-5′a),3.81 (dd, J=3.6 & 12.4 Hz, 1H, H-5′b), 1.06 (s, 9H, t-Bu). ¹³C NMR(CDCl₃) δ 157.3, 157.1, 153.6, 137.5, 135.6, 135.4, 135.1, 133.3, 132.8,132.6, 130.1, 130.0, 127.9, 127.8, 127.4, 126.1, 125.8, 91.3, 87.3,65.1, 26.9, 19.2.

Example 9 β-D-2′,3′-Dideoxy-5-fluoro-N-(4-iodobenzoyl)cytidine (10)

To a solution of 8 (131 mg, 0.28 mmol) and DMAP (5 mg) in anhydrousCH₂Cl₂ (2 mL) and Et₃N (0.5 mL) at 0° C. was added 4-iodobenzoylchloride (85 mg, 0.31 mmol). The reaction mixture was stirred at 0° C.for 30 min, then at room temperature for another 3 h. After removal ofthe solvent by evaporation, the residue was mixed with THF (3 mL), andTBAF (1 M solution in THF, 0.28 mL, 0.28 mmol) was added. After stirringfor 2 h at room temperature, the solvent was evaporated, and the residuewas purified by flash chromatography on silica gel eluting withCH₂Cl₂/MeOH (96:4) to give, after recrystallization from CH₂Cl₂/hexane,the title compound 10 as a yellow powder (48 mg, 37%). ¹H NMR (DMSO-d₆)δ 8.9 (bs, 1H, NH), 7.90-7.73 (m, 5H, H-6, arom.), 5.91 (bs, 1H, H-1′),5.10 (m, 1H, OH), 4.14 (m, 1H, H-4′), 3.80, 3.57 (2m, 2H, H-5′), 2.35,2.08 (2m, 2H, H-2′), 1.86 (m, 2H, H-3′).

By following the same procedures as above but using the correspondingcarboxylic acid chloride starting materials, the following compounds arealso prepared:

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine (11)

¹H NMR (DMSO-d₆) δ 8.9 (bs, 1H, NH), 8.05, 7.34 (2m, 5H, H-6, arom.),5.90 (d, 1H, H-1′), 5.25 (m, 1H, OH), 4.11 (m, 1H, H-4′), 3.79, 3.58(2m, 2H, H-5′), 2.35, 2.08 (2m, 2H, H-2′), 1.85 (m, 2H, H-3′).

β-D-N⁴-(4-chlororobenzoyl)-2′,3′-dideoxy-5-fluorocytidine (12)

¹H NMR (DMSO-d₆) δ 8.9 (bs, 1H, NH), 7.99, 7.60 (2m, 5H, H-6, arom.),5.90 (bs, 1H, H-1′), 5.38 (m, 1H, OH), 4.14 (m, 1H, H-4′), 3.82, 3.58(2m, 2H, H-5′), 2.35, 2.08 (2m, 2H, H-2′), 1.84 (m, 2H, H-3′).

β-D-N⁴-(4-bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine (13)

¹H NMR (DMSO-d₆) δ 8.9 (bs, 1H, NH), 7.93, 7.72 (2m, 5H, H-6, arom.),5.91 (d, 1H, H-1′), 5.25 (m, 1H, OH), 4.11 (m, 1H, H-4′), 3.79, 3.58(2m, 2H, H-5′), 2.35, 2.07 (2m, 2H, H-2′), 1.85 (m, 2H, H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-(3-fluorobenzoyl)cytidine (14)

¹H NMR (CDCl₃) δ 8.37 (d, 1H, H-6), 8.09-7.24 (m, 4H, arom.), 6.08 (m,1H, H-1′), 4.27 (m, 1H, H-4′), 4.13, 3.82 (2d, 2H, H-5′), 2.48, 2.20(2m, 2H, H-2′), 2.02 (m, 2H, H-3′).

β-D-N⁴-(3-Chlorobenzoyl)-2′,3′-dideoxy-5-fluorocytidine (15)

¹H NMR (DMSO-d₆) δ 8.8 (bs, 1H, NH), 8.01-7.53 (m, 5H, H-6, arom.), 5.91(d, 1H, H-1′), 5.34 (t, 1H, OH), 4.12 (m, 1H, H-4′), 3.81, 3.58 (2d, 2H,H-5′), 2.40, 2.10 (2m, 2H, H-2′), 1.85 (m, 2H, H-3′).

β-D-N⁴-(3-Bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine (16)

¹H NMR (DMSO-d₆) δ 8.75 (bs, 1H, NH), 8.14-7.45 (m, 5H, H-6, arom.),5.90 (d, 1H, H-1′), 5.29 (bs, 1H, OH), 4.11 (m, 1H, H-4′), 3.80, 3.58(2m, 2H, H-5′), 2.40, 2.08 (2m, 2H, H-2′), 1.85 (m, 2H, H-3′).

β-D-N⁴-p-Anisoyl-2′,3′-dideoxy-5-fluorocytidine (17)

¹H NMR (DMSO-d₆) δ8.1 (bs, 1H, NH), 7.97, 7.04 (2m, 5H, H-6, arom.),5.95 (m, 1H, H-1′), 4.50 (m, 1H, OH), 4.40 (m, 1H, H-4′), 3.82 (s, 3H,CH₃), 3.80 (m, 2H, H-5′), 2.35, 2.05 (2m, 2H, H-2′), 1.90 (m, 2H, H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-(4-nitrobenzoyl)cytidine (18)

¹H NMR (DMSO-d₆) δ8.9 (bs, 1H, NH), 8.32, 8.23 (2m, 5H, H-6, arom.),5.92 (d, 1H, H-1′), 5.30 (bs, 1H, OH), 4.11 (m, 1H, H-4′), 3.79, 3.59(2m, 2H, H-5′), 2.35, 2.10 (2m, 2H, H-2′), 1.86 (m, 2H, H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N-(3-nitrobenzoyl)cytidine (19)

¹H NMR (DMSO-d₆) δ8.76 (d, 1H, H-6), 8.7 (bs, 1H, NH), 8.40, 7.80 (2m,4H, arom.), 5.95 (d, 1H, H-1′), 5.30 (m, 1H, OH), 4.08 (m, 1H, H-4′),3.79, 3.58 (2m, 2H, H-5′), 2.35, 2.08 (2m, 2H, H-2′), 1.85 (m, 2H,H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-(2-nitrobenzoyl)cytidine (20)

¹H NMR (CDCl₃) δ8.49 (d, 1H, H-6), 7.96-7.50 (m, 4H, arom.), 6.02 (d,1H, H-1′), 4.22 (m, 1H, H-4′), 4.11, 3.81 (2d, 2H, H-5′), 2.45, 2.15(2m, 2H, H-2′), 1.98 (m, 2H, H-3′).

β-D-N⁴-Benzoyl-2′,3′-dideoxy-5-fluorocytidine (21)

¹H NMR (DMSO-d₆) δ8.2 (bs, 1H, NH), 7.98, 7.52 (2m, 5H, H-6, arom.),5.95 (d, 1H, H-1′), 5.74 (bs, 1H, OH), 4.57, 4.40 (2m, 3H, H-4′, H-5′),2.35, 2.08 (2m, 2H, H-2′), 1.90 (m, 2H, H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-p-toluoylcytidine (22)

¹H NMR (CDCl₃) δ 8.31 (d, 1H, H-6), 8.15, 7.24 (2m, 4H, arom.), 6.08 (m,1H, H-1′), 4.25 (m, 1H, H-4′), 4.10, 3.82 (2m, 2H, H-5′), 2.42 (s, 3H,CH₃), 2.47, 2.15 (2m, 2H, H-2′), 2.00 (m, 2H, H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-m-toluoylcytidine (23)

¹H NMR (CDCl₃) δ 8.31 (d, 1H, H-6), 8.07, 7.36 (2m, 4H, arom.), 6.09 (m,1H, H-1′), 4.25 (m, 1H, H-4′), 4.11, 3.83 (2m, 2H, H-5′), 2.45, 2.18(2m, 2H, H-2′), 2.42 (s, 3H, CH₃), 2.00 (m, 2H, H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-o-toluoylcytidine (24)

¹H NMR (DMSO-d₆) δ8.8 (bs, 1H, NH), 7.55-7.26 (m, 6H, H-6, arom.), 5.88(d, 1H, H-1′), 5.30 (t, 1H, OH), 4.12 (m, 1H, H-4′), 3.82, 3.58 (2m, 2H,H-5′), 2.41 (s, 3H, CH₃), 2.32, 2.07 (2m, 2H, H-2′), 1.83 (m, 2H, H-3′).

β-D-2′,3′-Dideoxy-N⁴-(4-ethylbenzoyl)-5-fluorocytidine (25)

¹H NMR (CDCl₃) δ8.24 (d, 1H, H-6), 8.18, 7.29 (2m, 4H, arom.), 6.10 (d,1H, H-1′), 4.24 (m, 1H, H-4′), 4.10, 3.80 (2m, 2H, H-5′), 2.72 (q, 2H,CH₂), 2.50, 2.20 (2m, 2H, H-2′), 2.00 (m, 2H, H-3′), 1.26 (t, 3H, CH₃).

β-D-2′,3′-Dideoxy-5-fluoro-N-(4-n-propylbenzoyl)cytidine (26)

¹H NMR (CDCl₃) δ8.30 (d, 1H, H-6), 8.17, 7.25 (2m, 4H, arom.), 6.09 (m,1H, H-1′), 4.24 (m, 1H, H-4′), 4.11, 3.80 (2m, 2H, H-5′), 2.65 (t, 2H,CH₂), 2.45, 2.18 (2m, 2H, H-2′), 2.02 (m, 2H, H-3′), 1.66 (m, 2H, CH₂),0.94 (t, 3H, CH₃).

β-D-N-(4-n-Butylbenzoyl)-2′3′-dideoxy-5-fluorocytidine (27)

¹H NMR (CDCl₃) δ8.34 (d, 1H, H-6), 8.17, 7.25 (2m, 4H, arom.), 6.10 (m,1H, H-1′), 4.25 (m, 1H, H-4′), 4.13, 3.82 (2m, 2H, H-5′), 2.68 (t, 2H,CH₂), 2.50, 2.20 (2m, 2H, H-2′), 2.02 (m, 2H, H-3′), 1.66 (m, 2H, CH₂),1.37 (m, 2H, CH₂), 0.93 (t, 3H, CH₃).

β-D-N⁴-(4-tert-Butylbenzoyl)-2′,3′-dideoxy-5-fluorocytidine (28)

¹H NMR (CDCl₃) δ8.31 (d, 1H, H-6), 8.17, 7.48 (2m, 4H, arom.), 6.08 (m,1H, H-1′), 4.25 (m, 1H, H-4′), 4.10, 3.80 (2m, 2H, H-5′), 2.47, 2.15(2m, 2H, H-2′), 2.00 (m, 2H, H-3′), 1.35 (s, 9H, t-Bu).

β-D-2′3′-Dideoxy-5-fluoro-N⁴-(2-furoyl)cytidine (29)

¹H NMR (CDCl₃) δ 8.37 (d, 1H, H-6), 7.62, 7.38, 6.52 (3m, 3H, furoyl),6.07 (m, 1H, H-1′), 4.25 (m, 1H, H-4′), 4.11, 3.80 (2m, 2H, H-5′), 2.47,2.17 (2m, 2H, H-2′), 2.01 (m, 2H, H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-(2-thiophenecarbonyl)cytidine (30)

¹H NMR (CDCl₃) δ8.32 (d, 1H, H-6), 7.96 (d, 1H, thiophenyl), 7.60 (d,1H, thiophenyl), 7.13 (t, 1H, thiophenyl), 6.08 (m, 1H, H-1′), 4.25 (m,1H, H-4′), 4.13, 3.82 (2m, 2H, H-5′), 2.47, 2.17 (2m, 2H, H-2′), 2.02(m, 2H, H-3′). β-D-2′,3′-Dideoxy-5-fluoro-N⁴-(nicotinoyl)cytidine (31)

¹H NMR (CDCl₃) δ 9.11 (s, 1H, nicotinoyl), 8.53 (d, 1H, H-6), 8.75,8.54, 7.40 (3m, 3H, nicotinoyl), 6.10 (m, 1H, H-1′), 4.27 (m, 1H, H-4′),4.16, 3.83 (2m, 2H, H-5′), 2.48, 2.20 (2m, 2H, H-2′), 2.03 (m, 2H,H-3′).

β-D-2′,3′-Dideoxy-5-fluoro-N⁴-(benzo[b]thiophene-2-carbonyl)cytidine(32)

¹H NMR (DMSO-d₆) δ8.7 (bs, 1H, NH), 8.00, 7.45 (2m, 6H, H-6, arom.),5.91 (d, 1H, H-1′), 5.32 (m, 1H, OH), 4.11 (m, 1H, H-4′), 3.80, 3.58(2m, 2H, H-5′), 2.44, 2.08 (2m, 2H, H-2′), 1.86 (m, 2H, H-3′).

β-D-N⁴-(Cyclohexanecarbonyl)-2′,3′-dideoxy-5-fluorocytidine (33)

¹H NMR (CDCl₃) δ 8.45 (d, 1H, H-6), 6.04 (d, 1H, H-1′), 4.25 (m, 1H,H-4′), 4.12, 3.81 (2m, 2H, H-5′), 2.50-1.20 (m, 15H, H-2′, H-3′,c-hexyl).

Example 10 β-D-N⁴-Butyryl-2′,3′-dideoxy-5-fluorocytidine (34)

To a solution of 8 (131 mg, 0.28 mmol) and DMAP (5 mg) in anhydrousCH₂Cl₂ (2 mL) and Et₃N (6.5 mL) at 0° C. was added butyric anhydride (52mg, 0.33 mmol). The reaction mixture was stirred at 0° C. for 30 min,then at room temperature for another 2 h. After removal of the solventby evaporation, the residue was mixed with THF (3 mL), and TBAF (1 Msolution in THF, 0.30 mL, 0.30 mmol) was added. After stirring for 2 h,at room temperature, the solvent was evaporated, and the residue waspurified by flash chromatography on silica gel eluting with CH₂Cl₂/MeOH(96:4) to give, after recrystallization from CH₂Cl₂/hexane, the titlecompound 34 as a white solid (31 mg, 35%). ¹H NMR (DMSO-d₆) δ 8.21 (d,1H, H-6), 5.92 (t, 1H, H-1′), 4.26 (m, 1H, H-4′), 4.22 (m, 2H, H-5′),2.30 (t, 2H, CH₂), 2.38, 2.04 (2m, 2H, H-2′), 1.90 (m, 2H, H-3′), 1.58(m, 2H, CH₂), 0.85 (t, 3H, CH₃).

Example 11β-D-2,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine(35)

To a solution of 9 (140 mg, 0.3 mmol) and DMAP (5 mg) in anhydrousCH₂Cl₂ (2 mL) and Et₃N (0.5 mL) at 0° C. was added 4-fluorobenzoylchloride (52 mg, 0.33 mmol). The reaction mixture was stirred at 0° C.for 30 min, then at room temperature for another 2 h. After removal ofthe solvent by evaporation, the residue was mixed with THF (3 mL), andTBAF (1 M solution in THF, 0.30 mL, 0.30 mmol) was added. After stirringfor 2 h at room temperature, the solvent was evaporated, and the residuewas purified by flash chromatography on silica gel eluting withCH₂Cl₂/MeOH (96:4) to give, after recrystallization from CH₂Cl₂/hexane,the title compound 35 as a pale yellow solid (33 mg, 32%). ¹H NMR(DMSO-d₆) δ 8.07, 7.35 (2m, 5H, H-6, arom.), 6.84 (bs, 1H, H-1′), 6.42(m, 1H, H-2′), 5.98 (m, 1H, H-3′), 5.22 (m, 1H, OH), 4.88 (m, 1H, H-4′),3.66 (m, 2H, H-5′).

By following the same procedures as above but using the correspondingcarboxylic acid chloride starting materials, the following compounds arealso prepared:

β-D-N⁴-(4-Chlorobenzoyl)-2′,3′-didehydro-2,3′-dideoxy-5-fluorocytidine(36)

¹H NMR (DMSO-d₆) S8.00, 7.59 (2m, 5H, H-6, arom.), 6.84 (bs, 1H, H-1′),6.42 (m, 1H, H-2′), 5.97 (m, 1H, H-3′), 5.22 (m, 1H, OH), 4.88 (m, 1H,H-4′), 3.66 (m, 2H, H-5′).

β-D-N⁴-(4-Bromobenzoyl)-2,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine(37)

¹H NMR (DMSO-d₆) δ 7.86, 7.72 (2m, 5H, H-6, arom.), 6.85 (bs, 1H, H-1′),6.42 (m, 1H, H-2′), 5.97 (m, 1H, H-3′), 4.88 (m, 1H, H-4′), 3.90-3.65(m, 2H, H-5′).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidine(38)

¹H NMR (DMSO-d₆) δ 7.90-7.60 (2m, 5H, H-6, arom.), 6.83 (bs, 1H, H-1′),6.42 μm, 1H, H-2′), 5.97 (m, 1H, H-3′), 5.22 (m, 1H, OH), 4.88 (m, 1H,H-4′), 3.66 (m, 2H, H-5′).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(3-fluorobenzoyl)cytidine(39)

¹H NMR (DMSO-d₆) δ 7.85-7.39 (m, 5H, H-6, arom.), 6.84 (bs, 1H, H-1′),6.42 (m, 1H, H-2′), 5.98 (m, 1H, H-3′), 5.22 (m, 1H, OH), 4.88 (m, 1H,H-4′), 3.66 (m, 2H, H-5′).

β-D-N⁴-(3-Chlorobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine(40)

¹H NMR (DMSO-d₆) δ 8.00-7.40 (2m, 5H, H-6, arom.), 6.84 (bs, 1H, H-1′),6.42 (m, 1H, H-2′), 5.97 (m, 1H, H-3′), 5.22 (m, 1H, OH), 4.88 (m, 1H,H-4′), 3.66 (m, 2H, H-5′).

β-D-N⁴-(3-Bromobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine(41)

¹H NMR (DMSO-d₆) δ8.16-7.34 (m, 5H, H-6, arom.), 6.84 (bs, 1H, H-1′),6.46 (m, 1H, H-2′), 5.98 (m, 1H, H-3′), 5.23 (t, 1H, OH), 4.88 (bs, 1H,H-4′), 3.68 (m, 2H, H-5′).

β-D-N⁴-p-Anisoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (42)

¹H NMR (CDCl₃+DMSO-d₆) δ 7.72 (d, 2H, arom.), 7.12 (d, J=7.2 Hz, 1H,H-6), 6.93 (m, 1H, H-1′), 6.48 (d, 2H, arom.), 6.45 (m, 1H, H-2′), 5.87(m, 1H, H-3′), 5.78 (m, 1H, H-4′), 4.03 (s, 3H, OCH₃), 3.40 (m, 2H,H-5′).

β-D-N⁴-m-Anisoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (43)

¹H NMR (CDCl₃) δ 7.35-6.60 (m, 5H, H-6, H-1′, arom.), 6.60 (m, 1H,arom.), 6.58 (m, 1H, H-2′), 5.82 (m, 1H, H-3′), 5.74 (m, 1H, H-4′), 3.99(s, 3H, OCH₃), 3.36 (m, 2H, H-5′).

β-D-N⁴-o-Anisoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (44)

¹H NMR (DMSO-d₆) δ10.75 (bs, 1H, NH), 8.55 (d, 1H, H-6), 7.77-7.08 (m,4H, arom.), 6.84 (bs, 1H, H-1′), 6.40 (m, 1H, H-2′), 5.99 (m, 1H, H-3′),5.19 (t, 1H, OH), 4.89 (m, 1H, H-4′), 3.91 (s, 3H, OCH₃), 3.66 (m, 2H,H-5′).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(4-nitrobenzoyl)cytidine(45)

¹H NMR (DMSO-d₆) δ8.34-8.20 (m, 5H, H-6, arom.), 6.83 (bs, 1H, H-1′),6.42 (m, 1H, H-2′), 5.95 (m, 1H, H-3′), 5.18 (m, 1H, OH), 4.87 (bs, 1H,H-4′), 3.66 (m, 2H, H-5′).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(3-nitrobenzoyl)cytidine(46)

¹H NMR (DMSO-d₆) δ 8.74-7.38 (m, 5H, H-6, arom.), 6.83 (bs, 1H, H-1′),6.42 (m, 1H, H-2′), 5.97 (m, 1H, H-3′), 5.18 (m, 1H, OH), 4.87 (bs, 1H,H-4′), 3.66 (m, 2H, H-5′).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(2-nitrobenzoyl)cytidine(47)

¹H NMR (DMSO-d₆) δ8.14-7.71 (m, 5H, H-6, arom.), 6.83 (bs, 1H, H-1′),6.42 (m, 1H, H-2′), 5.95 (m, 1H, H-3′), 5.18 (m, 1H, OH), 4.87 (bs, 1H,H-4′), 3.66 (m, 2H, H-5′).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-p-toluoylcytidine (48)

¹H NMR (DMSO-d₆) δ 7.87-7.31 (2m, 5H, H-6, arom.), 6.83 (m, 1H, H-1′),6.40 (m, 1H, H-2′), 5.95 (m, 1H, H-3′), 5.18 (m, 1H, OH), 4.85 (m, 1H,H-4′), 3.66 (m, 2H, H-5′), 2.37 (s, 3H, CH₃).

β-D-2′,3′-Didehydro-2,3′-dideoxy-5-fluoro-N⁴-m-toluoylcytidine (49)

¹H NMR (DMSO-d₆) δ 7.78, 7.42 (2m, 5H, H-6, arom.), 6.83 (bs, 1H, H-1′),6.41 (m, 1H, H-2′), 5.97 (m, 1H, H-3′), 5.17 (bs, 1H, OH), 4.87 (m, 1H,H-4′), 3.66 (m, 2H, H-5′), 2.36 (s, 3H, CH₃).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-o-toluoylcytidine (50)

¹H NMR (DMSO-d₆) δ7.60-7.40 (m, 5H, H-6, arom.), 6.83 (bs, 1H, H-1′),6.40 (m, 1H, H-2′), 5.99 (m, 1H, H-3′), 5.17 (bs, 1H, OH), 4.88 (m, 1H,H-4′), 3.66 (m, 2H, H-5′), 2.42 (s, 3H, CH₃).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-N⁴-(4-ethyllbenzoyl)-5-fluorocytidine(51)

¹H NMR (CDCl₃) 18.19 (m, 2H, arom.), 8.09 (d, 1H, H-6), 7.28 (m, 2H,arom.), 7.03 (m, 1H, H-1′), 6.39 (m, 1H, H-2′), 5.91 (m, 1H, H-3′), 5.20(m, 1H, OH), 4.97 (m, 1H, H-4′), 4.02-3.85 (m, 2H, H-5′), 2.71 (q, 2H,CH₂), 1.26 (t, 3H, CH₃).

β-D-N⁴-(4-n-Butylbenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-4-cytidine(52)

¹H NMR (CDCl₃) 18.19 (m, 2H, arom.), 8.12 (d, 1H, H-6), 7.26 (m, 2H,arom.), 7.04 (m, 1H, H-1′), 6.37 (m, 1H, H-2′), 5.92 (m, 1H, H-3′), 4.99(m, 1H, H-4′), 4.03-3.87 (m, 2H, H-5′), 2.68 (t, 2H, CH₂), 1.66 (m, 2H,CH₂), 1.36 (m, 2H, CH₂), 0.93 (t, 3H, CH₃).

βD-N⁴-(4-tert-Butylbenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine(53)

¹H NMR (CDCl₃) δ8.19 (m, 2H, arom.), 8.09 (d, 1H, H-6), 7.48 (m, 2H,arom.), 7.04 (m, 1H, H-1′), 6.36 (m, 1H, H-2′), 5.91 (m, 1H, H-3′), 5.22(m, 1H, OH), 4.98 (m, 1H, H-4′), 4.02-3.86 (m, 2H, H-5′), 1.34 (s, 9H,t-Bu).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(2-thiophenecarbonyl)cytidine(54)

¹H NMR (DMSO-d₆) δ 8.30-7.20 (m, 4H, H-6, thiophene), 6.82 (m, 1H,H-1′), 6.42 (m, 1H, H-2′), 5.93 (m, 1H, H-3′), 5.16 (m, 1H, OH), 4.85(m, 1H, H-4′), 3.65 (m, 2H, H-5′).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-nicotinoylcytidine (55)

¹H NMR (DMSO-d₆) δ 9.11-7.53 (m, 5H, H-6, nicotinoyl), 6.83 (bs, 1H,H-1′), 6.42 (d, 1H, H-2′), 5.95 (m, 1H, H-3′), 5.18 (m, 1H, OH), 4.88(m, 1H, H-4′), 3.66 (m, 2H, H-5′).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-[(benzo[b]thiophene-2-carbonyl)cytidine(56)

¹H NMR (DMSO-d₆) δ8.34-7.44 (m, 6H, H-6, arom.), 6.83 (bs, 1H, H-1′),6.41 (d, 1H, H-2′), 5.94 (m, 1H, H-3′), 5.18 (m, 1H, OH), 4.85 (m, 1H,H-4′), 3.66 (m, 2H, H-5′).

β-D-N⁴-(Cyclopentanecarbonyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine(57)

¹H NMR (DMSO-d₆) 10.60 (bs, 1H, NH), 8.48 (d, 1H, H-6), 6.81 (bs, 1H,H-1′), 6.38 (m, 1H, H-2′), 5.97 (m, 1H, H-3′), 5.16 (t, 1H, OH), 4.88(bs, 1H, H-4′), 3.65 (m, 2H, H-5′), 3.06 (m, 1H, CH), 1.85-1.51 (m, 8H,4 CH₂).

βD-N⁴-(Cyclohexanecarbonyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine(58)

¹H NMR (DMSO-d₆) δ 10.50 (bs, 1H, NH), 8.47 (d, 1H, H-6), 6.81 (d, 1H,H-1′), 6.38 (m, 1H, H-2′), 5.97 (m, 1H, H-3′), 5.16 (t, 1H, OH), 4.88(bs, 1H, H-4′), 3.65 (m, 2H, H-5′), 2.60 (m, 1H, CH), 1.81-1.17 (m, 10H,5 CH₂).

β-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluoro-N⁴-heptanoylcytidine (59)

¹H NMR (CDCl₃) δ 8.27 (d, 1H, H-6), 7.00 (bs, 1H, H-1′), 6.28 (m, 1H,H-2′), 5.99 (m, 1H, H-3′), 5.30 (bs, 1H, OH), 5.01 (bs, 1H, H-4′),4.03-3.86 (m, 2H, H-5′), 1.68, 1.30 (2 nm, 10H, 5 CH₂), 0.88 (t, 3H,CH₃).

Example 12 β-D-N⁴-Butyryl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine(60)

To a solution of 9 (140 mg, 0.3 mmol) and DMAP (5 mg) in anhydrousCH₂Cl₂ (2 mL) and Et₃N (0.5 mL) at 0° C. was added butyric anhydride (52mg, 0.33 mmol). The reaction mixture was stirred at 0° C. for 30 min,then at room temperature for another 2 h. After removal of the solventby evaporation, the residue was mixed with THF (3 mL), and TBAF (1 Msolution in THF, 0.30 mL, 0.30 mmol) was added. After stirring for 2 hat room temperature, the solvent was evaporated, and the residue waspurified by flash chromatography on silica gel eluting with CH₂Cl₂/MeOH(96:4) to give, after recrystallization from CH₄Cl₂/hexane, the titlecompound 60 as a white solid (31 mg, 35%). ¹H NMR (DMSO-d₆) δ 8.47 (d,1H, H-6), 6.82 (t, 1H, H-1′), 6.39 (m, 1H, H-2′), 5.98 (m, 1H, H-3′);5.20 (t, 1H, OH), 4.89 (m, 1H, H-4′), 3.66 (m, 2H, H-5′), 2.51 (t, 2H,CH₂), 1.58 (m, 2H, CH₂), 0.89 (t, 3H, CH₃).

Example 13 Anti-HIV (in PBM Cells) Assay

Anti-HIV-1 activity of the compounds was determined in human peripheralblood mononuclear (PBM) cells as described previously (Schinazi R. F.,McMillan A., Cannon D., Mathis R., Lloyd R. M. Jr., Peck A., SommadossiJ.-P., St. Clair M., Wilson J., Furman P. A., Painter G., Choi W.-B.,Liotta D. C. Antimicrob. Agents Chemother. 1992, 36, 2423; Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D., Xie M.-Y., Hart G., SmithG., Hahn E. Antimicrob. Agents Chemother. 1990, 34, 1061). Stocksolutions (20-40 mM) of the compounds were prepared in sterile DMSO andthen diluted to the desired concentration in growth medium. Cells wereinfected with the prototype HIV-1_(LAI) at a multiplicity of infectionof 0.01. Virus obtained from the cell supernatant was quantified on day6 after infection by a reverse transcriptase assay using(rA)_(n)•(dT)₁₂₋₁₈ as template-primer. The DMSO present in the dilutedsolution (<0.1%) had no effect on the virus yield. AZT was included aspositive control. The antiviral EC₅₀ and EC₉₀ were obtained from theconcentration-response curve using the median effective method describedpreviously (Chou T.-C. & Talalay P. Adv. Enzyme Regul. 1984, 22, 27-55;Belen'kii M. S. & Schinazi R. F. Antiviral Res. 1994, 25, 1-11).

Anti-HIV (in MT-2 Cells) Assay

In a second antiviral testing system, the potency of the compounds wasdetermined by measurement of viral RNA accumulation in HIV-1_(RF)infected MT-2 cells (Bacheler L T, Paul M, Otto M J, Jadhav P K, StoneBA & Miller JA (1994) An assay for HIV RNIn infected cell lysates, andits use for rapid evaluation of antiviral efficacy. Antivir. Chem.Chemother. 5:111-121). The virus titer was established to determine thedilution producing 15 to 30 ng/RNA per well of HIV RNIn 3 days ofinfection. HIV-1 RNA was quantified using biotinylated capture andalkaline phosphatase-derivatized reporter oligonucleotides as describedpreviously (Charvet A-S, Camplo M, Faury P, Graciet J C, Mourier N,Chemann J C & Kraus J L (1994) Inhibition of human immunodeficiencyvirus type 1 replication by phosphonoformate- andphosphonoacetate-2′,3′-dideoxy-3′-thiacytidine conjugates. J. Med. Chem.37:2216-2223). In a third system, the effect of analogs on thereplication of HIV-1_(NL4-3) was determined via the InterCompanyConsortium consensus p24 assay as previously described (Jadhav P K &MacKay M F (1997) Cyclic urea amide: HIV-1 protease inhibitors with lownanomolar potency against both wild types and protease inhibitorresistant mutants of HIV. J. Med. Chem. 40:181-190). Recombinant viruseswere recovered by transfecting the appropriate NL4-3 plasmid bylipofection. Virus stocks recovered 7 to 10 days post-transfection weretitered on MT-4 cells to determine if the dilution produced 1,000 to3,000 ng p24 in 4 days. This dilution was then used in drugsusceptibility assays, where drug was added 24 h post infection ofcells, and p24 quantified by ELISA 3 days later.

Example 14 Anti-HBV Assay

The anti-HBV activity of the compounds was determined by treating theAD-38 cell line carrying wild type HBV under the control of tetracycline(Ladner S. K., Otto M. J., Barker C. S., Zaifert K., Wang G. H., Guo J.T., Seeger C. & King R. W. Antimicrob. Agents Chemother. 1997, 41,1715-1720). Removal of tetracycline from the medium [Tet (−)] results inthe production of HBV. The levels of HBV in the culture supernatantfluids from cells treated with the compounds were compared with that ofthe untreated controls. Control cultures with tetracycline [Tet (+)]were also maintained to determine the basal levels of HBV expression.3TC was included as positive control (see Tables 1, 2).

Example 15 Cytotoxicity Assay

The toxicity of the compounds was assessed in Vero, human PBM, CEM(human lymphoblastoid), MT-2, and HepG2 cells, as described previously(Schinazi R. F., Sommadossi J.-P., Saalmann V., Cannon D. L., Xie M.-Y.,Hart G. C., Smith G. A. & Hahn E. F. Antimicrob Agents Chemother. 1990,34, 1061-1067). Cycloheximide was included as positive cytotoxiccontrol, and untreated cells exposed to solvent were included asnegative controls. The cytotoxicity IC₅₀ was obtained from theconcentration-response curve using the median effective method describedpreviously (Chou T.-C. & Talalay P. Adv. Enzyme Regzu. 1984, 22, 27-55;Belen'kii M. S. & Schinazi R. F. Antiviral Res. 1994, 25, 1-11) (seeTables 1, 2).

TABLE 1 Anti-HIV activity and cytotoxicity ofN⁴-acyl-2′,3′-dideoxy-5-fluorocytidine Anti-HIV-1 activity in Cmpd.different cells (EC₉₀, μM) Cytotoxicity in different cells (IC₅₀, μM)No. N⁴-substituent PBM MT-2 MT-4 PBM CEM Vero MT-2 HepG2 D-D2FC H 0.321.4 1.3 >100 >100 >100 >50 >100 10 p-IBz 0.019 0.0250.17 >100 >100 >100 >50 >100 11 p-FBz 0.027 0.32 0.61 >10045.7 >100 >50 >100 12 p-ClBz 0.02 0.22 0.37 >100 33.4 >100 >50 7.3 13p-BrBz 0.03 0.14 0.30 >100 31.6 >100 >50 >100 14 m-FBz 0.106 0.460.43 >100 80.8 >100 >50 >100 15 m-ClBz 0.08 0.4 0.51 >100 68.191.6 >50 >100 16 m-BrBz 0.145 0.51 0.42 >100 40.6 80.6 >50 >100 17p-MeOBz 8.31 6 69.2 31.6 5.3 16 4.5 18 p-NO₂Bz 0.18 0.40.30 >100 >100 >100 >50 >100 19 m-NO₂Bz 1.6 1.81.59 >100 >100 >100 >50 >100 20 o-NO₂Bz 1.5 0.7 >100 >100 >100 >50 >10021 Bz 1.29 1.2 67.0 38.5 5.8 19 15.3 22 p-MeBz 0.028 0.310.23 >100 >100 >100 >50 >100 23 m-MeBz 0.012 0.24 8.4 >100 61.1 >50 >10024 o-MeBz 1.2 6.8 20.6 22.5 39.6 >50 >100 25 p-EtBz 0.03 0.12 0.22 >10089.8 >100 50 >100 26 p-PrBz 0.017 0.1 0.22 >100 >100 >100 >50 >100 27p-BuBz 0.31 ND 1.1 1.3 3.2 ND 1.9 28 p-t-BuBz 0.088 0.6 ND 12.5 6.0 25.950 21.3 29 o-furoyl 1.5 0.9 ND 16.9 5.7 29.6 >50 31.1 30o-thiophenecarbonyl 0.052 0.4 ND 19.4 13.7 23.9 >50 37.9 31 Nicotinoyl0.17 5.9 ND 8.8 5.5 28.1 >50 19.4 32 benzo[b]thiophene- 0.19 0.3 ND 23.54.5 39.6 >50 1.3 2-carbonyl 33 c-hexanecarbonyl 0.086 0.3 ND 4.5 6.411.8 50 6.5 34 Butyryl 1.6 0.71 ND 17.1 31.6 5.8 7.2 7.6 ND = notdetermined

TABLE 2 Anti-HIV activity and cytotoxicity ofN⁴-acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine Anti-HIV-1activity in Compd. different cells (EC₉₀, μM) Cytotoxicity in differentcells (IC₅₀, μM) No. N⁴-substituent PBM MT-2 MT-4 PBM CEM Vero MT-2HepG2 D-D4FC H 0.77 1.19 1.15 >100 >100 >100 >50 >100 35 p-FBz 1.08 0.887.2 53.1 51.3 83.1 >50 93.6 36 p-ClBz 0.48 0.23 1.9 11.9 16.872.2 >50 >100 37 p-BrBz 1.4 0.14 5.2 53 24 40.5 >50 >100 38 p-IBz 0.760.31 0.85 57 11.4 100 >50 >100 39 m-FBz 7.82 1.0 3.1 45.34.2 >100 >50 >100 40 m-ClBz 1.71 2.0 3.4 45.3 11.2 100 >50 32.4 41m-BrBz 1.71 1.0 2.2 51.6 24.9 99.7 >50 >100 42 p-MeOBz 0.70 0.58 ND >100ND ND >50 >100 43 m-MeOBz 2.1 0.34 ND 18.5 24.6 >100 >50 >100 44 o-MeOBz14.6 >50 ND 13.1 3.9 5.6 >50 3.4 45 p-NO₂Bz 1.7 0.29 ND 3.4 4.2 6.6 >505.6 46 m-NO₂Bz 0.93 0.58 ND 11.9 54.5 >100 >50 >100 47 o-NO₂Bz 39.9 >50ND 80 >100 >100 >50 >100 48 p-MeBz 0.32 0.21 ND 13.2 31.9 >100 >50 >10049 m-MeBz 0.7 0.8 ND 57.1 34.9 149 >50 >100 50 o-MeBz 56.8 >50 ND 58.446.4 >100 >50 >100 51 p-EtBz 6.2 0.24 2.3 13 8.1 40.3 >50 >100 52 p-BuBz3.1 ND ND 7.3  8.5. 29.4 ND 5.1 53 p-tBuBz 0.41 0.13 1.1 5 9.959.2 >50 >100 54 o-thiophenecarbonyl 1.6 1.5 ND 10.2 3.9 4.8 >50 2.3 55Nicotinoyl 42.3 29 ND 13.8  6.7. 13.1 >50 10.3 56 benzo[b]thiophene-0.29 0.3 ND 2.2 2.8 5.6 >50 1.3 2-carbonyl 57 cyclopentanecarbonyl 0.400.51 ND 52.9 19.6 87.6 >50 >100 58 Cyclohexanecarbonyl 0.6 0.38 ND 11.711.2 >100 >50 >100 59 Heptanoyl ND 0.23 ND ND ND ND 6.2 ND 60 Butyryl1.89 2.4 3.1 52.4 12.2 >100 >50 >100 ND = not determined

1. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein X is O, S, NR⁵,CH₂, CHF or CF₂; R¹ is chosen from hydrogen, halogen, alkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF₃, N₃,NO₂, aryl, heteroaryl and acyl; R² is chosen from alkenyl, alkynyl,cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl,heteroaryl, and C₆H₄R⁶ where R⁶ is chosen from halogen, CN, CF₃, N₃,NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl,and aryl; R³ and R^(3′) are chosen independently from H, halogen, CN,CF₃, N₃, NO₂, alkyl, alkenyl, and alkynyl; and R⁴ is H, phosphate,carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or otherpharmaceutically acceptable leaving group, which, when administered invivo, is capable of providing a compound wherein R³ and R^(3′) are H orphosphate, sulfonate ester, a lipid, an amino acid, a peptide, orcholesterol. R⁵ is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.
 2. Apharmaceutical composition that comprises an effective HIV or HBVtreatment amount of a compound of claim 1 in a pharmaceuticallyacceptable carrier or diluent.
 3. A method for the treatment of a hostinfected with HIV that comprises administering an effective amount of acompound of claim 1 in a pharmaceutically acceptable carrier.
 4. Amethod for the treatment of a host infected with HBV that comprisesadministering an effective amount of a compound of claim 1 in apharmaceutically acceptable carrier.
 5. A method for the treatment of ahost infected with HIV that comprises administering an effective amountof a compound of claim 1 in a pharmaceutically acceptable carrier incombination with another anti-HIV agent.
 6. A method for the treatmentof a host infected with HBV that comprises administering an effectiveamount of a compound of claim 1 in a pharmaceutically acceptable carrierin combination with another anti-HBV agent.
 7. The compound of claim 1wherein R¹ is hydrogen or fluorine.
 8. The compound of claim 1 whereinR³ is H or fluorine and R^(3′) is H.
 9. The method of claim 3, whereinR¹ is hydrogen or fluorine.
 10. The method of claim 3, wherein R³ is Hor fluorine and R^(3′) is H.
 11. (canceled)
 12. The compound of claim 1selected from the group consisting ofβ-D-N⁴-p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-chlorobenzoyl-2′,3′-didehydro-2′3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,andβ-D-N⁴-p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.13. (canceled)
 14. The pharmaceutical composition of claim 2 wherein thecompound is selected from the group consisting ofβ-D-N⁴-p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-chlorobenzoyl-2′,3′-didehydro-2′3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,andβ-D-N⁴-p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.15. (canceled)
 16. The method of claim 3 wherein the compound isselected from the group consisting ofβ-D-N⁴-p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-chlorobenzoyl-2′,3′-didehydro-2′3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,β-D-N⁴-p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,andβ-D-N⁴-p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.17. A compound selected from the following, or its pharmaceuticallyacceptable salt: β-D-2′,3′-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidineof the structure:

β-D-2′,3′-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine of thestructure:

β-D-N⁴-(4-chlorobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of thestructure:

β-D-N⁴-(4-bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:

β-D-2′,3′-dideoxy-5-fluoro-N⁴-(3-fluorobenzoyl)cytidine of thestructure:

β-D-N⁴-(3-chlorobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of thestructure:

β-D-N⁴-(3-bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:

β-D-2′,3′-dideoxy-5-fluoro-N⁴-(4-nitrobenzoyl)cytidine of the structure:

β-D-2′,3′-dideoxy-5-fluoro-N⁴-p-toluoylcytidine of the structure:

β-D-2′,3′-dideoxy-5-fluoro-N⁴-(m-toluoyl)cytidine of the structure:

β-D-2′,3′-dideoxy-N⁴-(4-ethylbenzoyl)-5-fluorocytidine of the structure:

β-D-2′,3′-dideoxy-5-fluoro-N⁴-(4-propylbenzoyl)cytidine of thestructure:

β-D-N⁴-(4-tert-butylbenzoyl)-2′,3′-dideoxy-5-fluorocytidine of thestructure:

β-D-2′,3′-dideoxy-5-fluoro-N⁴-(2-thiophenecarbonyl)cytidine of thestructure:

β-D-N⁴-(benzo-[b]-thiophene-2-carbonyl)-2′,3′-dideoxy-5-fluorocytidineof the structure:

β-D-N⁴-(cyclohexane-carbonyl)-2′,3′-dideoxy-5-fluorocytidine of thestructure:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidine ofthe structure:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidineof the structure:

β-D-N⁴-(4-chlorobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

β-D-N⁴-(4-bromobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

β-D-N⁴-p-anisoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of thestructure:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-(3-nitrobenzoyl)cytidineof the structure:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-p-toluoylcytidine of thestructure:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N⁴-m-toluoylcytidine of thestructure:

β-D-N⁴-(4-t-butylbenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

or a pharmaceutically acceptable salt thereof.β-D-N⁴-cyclopentanecarbonyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:

or a pharmaceutically acceptable salt thereof.β-D-N⁴-(cyclohexanecarbonyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidineof the structure:


18. The method of claim 4 wherein R¹ is hydrogen or fluorine.
 19. Themethod of claim 4 wherein R³ is H or fluorine and R^(3′) is H.
 20. Acompound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein i) X is O, S,NR⁵, CH₂, CHF or CF₂; ii) Y is CH₂, CHF or CF₂; iii) R¹ is chosen fromhydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, cycloalkyl, CN, CF₃, N₃, NO₂, aryl, heteroaryl and acyl;iv) R² is chosen from alkenyl, alkynyl, cycloalkyl, aminoalkyl,hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C₆H₄R⁶ whereR⁶ is chosen from halogen, CN, CF₃, N₃, NO₂, alkyl, haloalkyl,aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl; v) R³ andR^(3′) are chosen independently from H, halogen, CN, CF₃, N₃, NO₂,alkyl, alkenyl, and alkynyl; and vi) R⁴ is H, phosphate, carbonylsubstituted with alkyl, alkenyl, alkynyl, aryl, or otherpharmaceutically acceptable leaving group, which, when administered invivo, is capable of providing a compound wherein R³ and R^(3′) are H orphosphate, sulfonate ester, a lipid, an amino acid, a peptide, orcholesterol. vii) R⁵ is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.21. A pharmaceutical composition that includes an effective HIV or HBVtreatment amount of a compound of claim 20 in a pharmaceuticallyacceptable carrier or diluent.
 22. A method for the treatment of a hostinfected with HIV that includes administering an effective amount of acompound of claim 20 in a pharmaceutically acceptable carrier.
 23. Amethod for the treatment of a host infected with HBV that includesadministering an effective amount of a compound of claim 20 in apharmaceutically acceptable carrier.
 24. A method for the treatment of ahost infected with HIV that includes administering an effective amountof a compound of claim 20 in a pharmaceutically acceptable carrier incombination with another anti-HIV agent.
 25. A method for the treatmentof a host infected with HBV that includes administering an effectiveamount of a compound of claim 20 in a pharmaceutically acceptablecarrier in combination with another anti-HBV agent.
 26. A compound ofclaim 20 for use in the treatment of host infected with HIV.
 27. Acompound of claim 20 for use in the treatment of a host infected withHBV infection.